Description

BACKGROUND OF THE INVENTION

[0001]

1. Field of the Invention

[0002]

The present invention relates generally to pharmaceutical compositions, methods, and devices, and more specifically, to compositions and methods which reduce the likelihood of an infection associated with a medical implant.

[0003]

2. Description of the Related Art

[0004]

Infections associated with medical implants represent a major healthcare problem. For example, 5% of patients admitted to an acute care facility develop a hospital acquired infection. Hospital acquired infections (nosocomial infections) are the 11th leading cause of death in the US and cost over $2 billion annually. Nosocomial infections directly cause 19,000 deaths per year in the US and contribute to over 58,000 others.

[0005]

The four most common causes of nosocomial infections are: urinary tract infection (28%); surgical site infection (19%); respiratory tract infection (17%); and bloodstream infection (16% and rising). A significant percentage of these infections are related to bacterial colonization of implanted medical implants such as Foley catheters (urinary tract infections); surgical drains, meshes, sutures, artificial joints, vascular grafts (wound infections); endotracheal and tracheostomy tubes (respiratory tract infection); and vascular infusion catheters (bloodstream infections). Although any infectious agent can infect medical implant, Staphylococci (S. aureus, S. epidermidis, S. pyogenes), Enterococci (E. coli), Gram Negative Aerobic Bacilli, and Pseudomonas aeruginosa are common causes. Once a medical implant becomes colonized by bacteria, it must frequently be replaced resulting in increased morbidity for the patient and increased cost to the healthcare system. Often the infected device serves as a source for a disseminated infection which can lead to significant morbidity or even death.

[0006]

In an attempt to combat this important clinical problem, devices have been coated with antimicrobial drugs. Representative examples include U.S. Pat. No. 5,520,664 (“Catheter Having a Long-Lasting Antimicrobial Surface Treatment”), U.S. Pat. No. 5,709,672 (“Silastic and Polymer-Based Catheters with Improved Antimicrobial/Antifungal Properties”), U.S. Pat. No. 6,361,526 (“Antimicrobial Tympanostomy Tubes”), U.S. Pat. No. 6,261,271 (“Anti-infective and antithrombogenic medical articles and method for their preparation”), U.S. Pat. No. 5,902,283 (“Antimicrobial impregnated catheters and other medical implants”) U.S. Pat. No. 5,624,704 (“Antimicrobial impregnated catheters and other medical implants and method for impregnating catheters and other medical implants with an antimicrobial agent”) and U.S. Pat. No. 5,709,672 (“Silastic and Polymer-Based Catheters with Improved Antimicrobial/Antifungal Properties”).

[0007]

One difficulty with these devices, however, is that they can become colonized by bacteria resistant to the antibiotic coating. This can result in at least two distinct clinical problems. First, the device serves as a source of infection in the body with the resulting development of a local or disseminated infection. Secondly, if an infection develops, it cannot be treated with the antibiotic(s) used in the device coating. The development of antibiotic-resistant strains of microbes remains a significant healthcare problem, not just for the infected patient, but also for the healthcare institution in which it develops.

[0008]

Thus, there is a need in the art for medical implants which have a reduced likelihood of an associated infection. The present invention discloses such devices (as well as compositions and methods for making such devices) which reduce the likelihood of infections in medical implants, and further, provides other, related advantages.

BRIEF DESCRIPTION OF THE DRAWING

[0009]

[0009]FIG. 1 shows the effect of palmitic acid on the release profile of 5-fluorouracil from a polyurethane sample.

BRIEF SUMMARY OF THE INVENTION

[0010]

Briefly stated, the present invention provides compositions and methods for preventing, reducing or inhibiting the likelihood of infections associated with medical implants. More specifically, within one aspect of the invention medical implants or devices are provided which release a chemotherapeutic agent, wherein the chemotherapeutic agent reduces, inhibits, or prevents the growth or transmission of foreign organisms (e.g., bacteria, fungi, or viruses) which are on or are associated with the medical device or implant. For example, within one aspect of the invention medical implant or devices are provided which release an anthracycline, fluoropyrimidine, folic acid antagonist, podophylotoxin, camptothecin, hydroxyurea, or platinum complex. Within various embodiments, the implant is coated in whole or in part with a composition comprising an anthracycline, fluoropyrimidine, folic acid antagonist, podophylotoxin, camptothecin, hydroxyurea, or platinum complex.

[0011]

Other aspects of the present invention provide methods for making medical implants, comhprising adapting a medical implant (e.g., coating the implant) with an anthracycline, fluoropyrimidine, folic acid antagonist, podophylotoxin, camptothecin, hydroxyurea, or platinum complex. Within certain embodiments, the desired therapeutic agent is coated on and/or released from the medical implant at a dosage and/or concentration which is less than the typical dosage and/or concentration of the agent when used in the treatment of cancer.

Within further aspects of the invention, there is provided a catheter which releases an agent selected from the group consisting of an anthracycline, fluoropyrimidine, folic acid antagonist, podophylotoxin, camptothecin, hydroxyurea, or platinum complex. In one embodiment, the catheter releases a fluoropyrimidine and in still another embodiment the fluoropyrimidine is 5-FU. In other embodiments, the catheter further comprises a polymer wherein the agent is released from a polymer on the catheter. In certain embodiments, the catheter has a polymer that is polyurethane or poly(lactide-co-glycolide) (PLG). In related embodiments, the catheter is a vascular catheter or a dialysis catheter. In still other embodiments, the catheter relaeases an agent that is present on the catheter at a concentration which is less than the typical dosage and/or concentration that is used in the treatment of cancer.

[0014]

Within further aspects of the invention, there is provided a heart valve which releases an agent selected from the group consisting of an anthracycline, fluoropyrimidine, folic acid antagonist, podophylotoxin, camptothecin, hydroxyurea, or platinum complex. In one embodiment, the heart valve releases a fluoropyrimidine and in still another embodiment the fluoropyrimidine is 5-FU. In other embodiments, the heart valve further comprises a polymer wherein the agent is released from a polymer on the heart valve. In certain embodiments, the heart valve has a polymer that is polyurethane or PLG. In related embodiments, the heart valve is a prosthetic heart valve. In still other embodiments, the heart valve relaeases an agent that is present on the heart valve at a concentration which is less than the typical dosage and/or concentration that is used in the treatment of cancer.

[0015]

Within further aspects of the invention, there is provided a cardiac pacemaker which releases an agent selected from the group consisting of an anthracycline, fluoropyrimidine, folic acid antagonist, podophylotoxin, camptothecin, hydroxyurea, or platinum complex. In one embodiment, the cardiac pacemaker releases a fluoropyrimidine and in still another embodiment the fluoropyrimidine is 5-FU. In other embodiments, the cardiac pacemaker further comprises a polymer wherein the agent is released from a polymer on the cardiac pacemaker. In certain embodiments, the cardiac pacemaker has a polymer that is polyurethane or PLG. In still other embodiments, the cardiac pacemaker relaeases an agent that is present on the cardiac pacemaker at a concentration which is less than the typical dosage and/or concentration that is used in the treatment of cancer.

[0016]

Within further aspects of the invention, there is provided a implantable cardioverter defibrillator which releases an agent selected from the group consisting of an anthracycline, fluoropyrimidine, folic acid antagonist, podophylotoxin, camptothecin, hydroxyurea, or platinum complex. In one embodiment, the implantable cardioverter defibrillator releases a fluoropyrimidine and in still another embodiment the fluoropyrimidine is 5-FU. In other embodiments, the implantable cardioverter defibrillator further comprises a polymer wherein the agent is released from a polymer on the implantable cardioverter defibrillator. In certain embodiments, the implantable cardioverter defibrillator has a polymer that is polyurethane or PLG. In still other embodiments, the implantable cardioverter defibrillator relaeases an agent that is present on the implantable cardioverter defibrillator at a concentration which is less than the typical dosage and/or concentration that is used in the treatment of cancer.

[0017]

Within further aspects of the invention, there is provided a graft which releases an agent selected from the group consisting of an anthracycline, fluoropyrimidine, folic acid antagonist, podophylotoxin, camptothecin, hydroxyurea, or platinum complex. In one embodiment, the graft releases a fluoropyrimidine and in still another embodiment the fluoropyrimidine is 5-FU. In other embodiments, the graft further comprises a polymer wherein the agent is released from a polymer on the graft. In certain embodiments, the graft has a polymer that is polyurethane or PLG. In related embodiments, the graft is a vascular graft or a hemodialysis access graft. In still other embodiments, the graft relaeases an agent that is present on the graft at a concentration which is less than the typical dosage and/or concentration that is used in the treatment of cancer.

[0018]

Within further aspects of the invention, there is provided a ear, nose, or throat implant which releases an agent selected from the group consisting of an anthracycline, fluoropyrimidine, folic acid antagonist, podophylotoxin, camptothecin, hydroxyurea, or platinum complex. In one embodiment, the ear, nose, or throat implant releases a fluoropyrimidine and in still another embodiment the fluoropyrimidine is 5-FU. In other embodiments, the ear, nose, or throat implant further comprises a polymer wherein the agent is released from a polymer on the ear, nose, or throat implant. In certain embodiments, the ear, nose, or throat implant has a polymer that is polyurethane or PLG. In related embodiments, the ear, nose, or throat implant is a tympanostomy tube or a sinus stent. In still other embodiments, the ear, nose, or throat implant relaeases an agent that is present on the ear, nose, or throat implant at a concentration which is less than the typical dosage and/or concentration that is used in the treatment of cancer.

[0019]

Within further aspects of the invention, there is provided a urological implant which releases an agent selected from the group consisting of an anthracycline, fluoropyrimidine, folic acid antagonist, podophylotoxin, camptothecin, hydroxyurea, or platinum complex. In one embodiment, the urological implant releases a fluoropyrimidine and in still another embodiment the fluoropyrimidine is 5-FU. In other embodiments, the urological implant further comprises a polymer wherein the agent is released from a polymer on the urological implant. In certain embodiments, the urological implant has a polymer that is polyurethane or PLG. In related embodiments, the urological implant is a urinary catheter, ureteral stent, urethral stent, bladder sphincter, or penile implant. In still other embodiments, the urological implant relaeases an agent that is present on the urological implant at a concentration which is less than the typical dosage and/or concentration that is used in the treatment of cancer.

[0020]

Within further aspects of the invention, there is provided a endotracheal or tracheostomy tube which releases an agent selected from the group consisting of an anthracycline, fluoropyrimidine, folic acid antagonist, podophylotoxin, camptothecin, hydroxyurea, or platinum complex. In one embodiment, the endotracheal or tracheostomy tube releases a fluoropyrimidine and in still another embodiment the fluoropyrimidine is 5-FU. In other embodiments, the endotracheal or tracheostomy tube further comprises a polymer wherein the agent is released from a polymer on the endotracheal or tracheostomy tube. In certain embodiments, the endotracheal or tracheostomy tube has a polymer that is polyurethane or PLG. In still other embodiments, the endotracheal or tracheostomy tube relaeases an agent that is present on the endotracheal or tracheostomy tube at a concentration which is less than the typical dosage and/or concentration that is used in the treatment of cancer.

[0021]

Within further aspects of the invention, there is provided a CNS shunt which releases an agent selected from the group consisting of an anthracycline, fluoropyrimidine, folic acid antagonist, podophylotoxin, camptothecin, hydroxyurea, or platinum complex. In one embodiment, the CNS shunt releases a fluoropyrimidine and in still another embodiment the fluoropyrimidine is 5-FU. In other embodiments, the CNS shunt further comprises a polymer wherein the agent is released from a polymer on the CNS shunt. In certain embodiments, the CNS shunt has a polymer that is polyurethane or PLG. In related embodiments, the CNS shunt is a ventriculopleural shunt, a VA shunt, or a VP shunt. In still other embodiments, the CNS shunt relaeases an agent that is present on the CNS shunt at a concentration which is less than the typical dosage and/or concentration that is used in the treatment of cancer.

[0022]

Within further aspects of the invention, there is provided a orthopedic implant which releases an agent selected from the group consisting of an anthracycline, fluoropyrimidine, folic acid antagonist, podophylotoxin, camptothecin, hydroxyurea, or platinum complex. In one embodiment, the orthopedic implant releases a fluoropyrimidine and in still another embodiment the fluoropyrimidine is 5-FU. In other embodiments, the orthopedic implant further comprises a polymer wherein the agent is released from a polymer on the orthopedic implant. In certain embodiments, the orthopedic implant has a polymer that is polyurethane or PLG. In related embodiments, the orthopedic implant is a prosthetic joint or fixation device. In still other embodiments, the orthopedic implant relaeases an agent that is present on the orthopedic implant at a concentration which is less than the typical dosage and/or concentration that is used in the treatment of cancer.

[0023]

Within further aspects of the invention, there is provided a ocular implant which releases an agent selected from the group consisting of an anthracycline, fluoropyrimidine, folic acid antagonist, podophylotoxin, camptothecin, hydroxyurea, or platinum complex. In one embodiment, the ocular implant releases a fluoropyrimidine and in still another embodiment the fluoropyrimidine is 5-FU. In other embodiments, the ocular implant further comprises a polymer wherein the agent is released from a polymer on the ocular implant. In certain embodiments, the ocular implant has a polymer that is polyurethane or PLG. In related embodiments, the ocular implant is an intraocular lens or a contact lens. In still other embodiments, the ocular implant relaeases an agent that is present on the ocular implant at a concentration which is less than the typical dosage and/or concentration that is used in the treatment of cancer.

[0024]

Within other aspects of the invention, compositions are provided comprising a polymer and an anthracycline, fluoropyrimidine, folic acid antagonist, podophylotoxin, camptothecin, hydroxyurea, or platinum complex, wherein said anthracycline, fluoropyrimidine, folic acid antagonist, podophylotoxin, camptothecin, hydroxyurea, or platinum complex is present in said composition at a concentration of less than any one of 10−4 M, 10−5 M, 10−6 M, or, 10−7 M.

[0025]

Also provided methods for reducing or inhibiting infection associated with a medical implant, comprising the step of introducing a medical implant into a patient which has been coated with an anthracycline, fluoropyrimidine, folic acid antagonist, podophylotoxin, camptothecin, hydroxyurea, or platinum complex.

[0026]

Within various embodiments of the above, the anthracycline is doxorubicin or mitoxantrone, the fluoropyrimidine is 5-fluorouracil, the folic acid antagonist is methotrexate, and the podophylotoxin is etoposide. Within further embodiments the composition further comprises a polymer.

[0027]

These and other aspects of the present invention will become evident upon reference to the following detailed description and attached drawings. In addition, various references are set forth herein which describe in more detail certain procedures or compositions (e.g., compounds or agents and methods for making such compounds or agents, etc.), and are therefore incorporated by reference in their entirety. When PCT applications are referred to it is also understood that the underlying or cited U.S. applications are also incorporated by reference herein in their entirety.

DETAILED DESCRIPTION OF THE INVENTION

[0028]

Prior to setting forth the invention, it may be helpful to an understanding thereof to set forth definitions of certain terms that will be used hereinafter.

As used herein, the term “about” or “consists essentially of” refers to ±15% of any indicated structure, value, or range. Any numerical ranges recited herein are to be understood to include any integer within the range and, where applicable (e.g., concentrations), fractions thereof, such as one tenth and one hundredth of an integer (unless otherwise indicated).

[0031]

Briefly, as noted above, the present invention discloses medical implants (as well as compositions and methods for making medical implants) which reduce the likelihood of infections in medical implants. More specifically, as noted above, infection is a common complication of the implantation of foreign bodies such as medical devices. Foreign materials provide an ideal site for micro-organisms to attach and colonize. It is also hypothesized that there is an impairment of host defenses to infection in the microenvironment surrounding a foreign material. These factors make medical implants particularly susceptible to infection and make eradication of such an infection difficult, if not impossible, in most cases.

[0032]

Medical implant failure as a result of infection, with or without the need to replace the implant, results in significant morbidity, mortality and cost to the healthcare system. Since there is a wide array of infectious agents capable of causing medical implant infections, there exists a significant unmet need for therapies capable of inhibiting the growth of a diverse spectrum of bacteria and fungi on implantable devices. The present invention meets this need by providing drugs that can be released from an implantable device, and which have potent antimicrobial activity at extremely low doses. Further, these agents have the added advantage that should resistance develop to the chemotherapeutic agent, the drug utilized in the coating would not be one which would be used to combat the subsequent infection (i.e., if bacterial resistance developed it would be to an agent that is not used as an antibiotic).

Briefly, a wide variety of agents (also referred to herein as ‘therapeutic agents’ or ‘drugs’) can be utilized within the context of the present invention, either with or without a carrier (e.g., a polymer; see section II below). Discussed in more detail below are (A) Anthracyclines (e.g., doxorubicin and mitoxantrone), (B) Fluoropyrimidines (e.g., 5-FU), (C) Folic acid antagonists (e.g., methotrexate), (D) Podophylotoxins (e.g., etoposide), (E) Camptothecins, (F) Hydroxyureas, and (G) Platinum complexes (e.g., cisplatin).

A. Anthracyclines

[0035]

Anthracyclines have the following general structure, where the R groups may be a variety of organic groups:

[0036]

According to U.S. Pat. No. 5,594,158, suitable R groups are as follows: R1 is CH3 or CH2OH; R2 is daunosamine or H; R3 and R4 are independently one of OH, NO2, NH2, F, Cl, Br, I, CN, H or groups derived from these; R5 is hydrogen, hydroxy, or methoxy; and R6-8 are all hydrogen. Alternatively, R5 and R6 are hydrogen and R7 and R8 are alkyl or halogen, or vice versa.

[0037]

According to U.S. Pat. No. 5,843,903, R1 may be a conjugated peptide. According to U.S. Pat. No. 4,296,105, R5 may be an ether linked alkyl group. According to U.S. Pat. No. 4,215,062, R5 may be OH or an ether linked alkyl group. R1 may also be linked to the anthracycline ring by a group other than C(O), such as an alkyl or branched alkyl group having the C(O) linking moiety at its end, such as —CH2CH(CH2—X)C(O)—R1, wherein X is H or an alkyl group (see, e.g., U.S. Pat. No. 4,215,062). R2 may alternately be a group linked by the functional group ═N—NHC(O)—Y, where Y is a group such as a phenyl or substituted phenyl ring. Alternately R3 may have the following structure:

[0038]

in which R9 is OH either in or out of the plane of the ring, or is a second sugar moiety such as R3. R10 may be H or form a secondary amine with a group such as an aromatic group, saturated or partially saturated 5 or 6 membered heterocyclic having at least one ring nitrogen (see U.S. Pat. No. 5,843,903). Alternately, R10 may be derived from an amino acid, having the structure —C(O)CH(NHR11)(R12), in which R11 is H, or forms a C3-4 membered alkylene with R12. R12 may be H, alkyl, aminoalkyl, amino, hydroxy, mercapto, phenyl, benzyl or methylthio (see U.S. Pat. No. 4,296,105).

In another aspect, the therapeutic agent is a fluoropyrimidine analog, such as 5-fluorouracil, or an analog or derivative thereof, including Carmofur, Doxifluridine, Emitefur, Tegafur, and Floxuridine. Exemplary compounds have the structures:

R1

R2

5-Fluorouracil

H

H

Carmofur

C(O)NH(CH2)5CH3

H

Doxifluridine

A1

H

Floxuridine

A2

H

Emitefur

CH2OCH2CH3

B

Tegafur

C

H

B

C

[0043]

Other suitable fluoropyrimidine analogs include 5-FudR (5-fluoro-deoxyuridine), or an analog or derivative thereof, including 5-iododeoxyuridine (5-ludR), 5-bromodeoxyuridine (5-BudR), Fluorouridine triphosphate (5-FUTP), and Fluorodeoxyuridine monophosphate (5-dFUMP). Exemplary compounds have the structures:

These compounds are believed to function as therapeutic agents by serving as antimetabolites of pyrimidine.

C. Folic Acid Antagonists

[0049]

In another aspect, the therapeutic agent is a folio acid antagonist, such as Methotrexate or derivatives or analogs thereof, including Edatrexate, Trimetrexate, Raltitrexed, Piritrexim, Denopterin, Tomudex, and Pteropterin. Methotrexate analogs have the following general structure:

[0050]

The identity of the R group may be selected from organic groups, particularly those groups set forth in U.S. Pat. Nos. 5,166,149 and 5,382,582. For example, R1 may be N, R2 may be N or C(CH3), R3 and R3′ may H or alkyl, e.g., CH3, R4 may be a single bond or NR, where R is H or alkyl group. R5,6,8 may be H, OCH3, or alternately they can be halogens or hydro groups. R7 is a side chain of the general structure:

[0051]

wherein n=1 for methotrexate, n=3 for pteropterin. The carboxyl groups in the side chain may be esterified or form a salt such as a Zn2+ salt. R9 and R10 can be NH2 or may be alkyl substituted.

In another aspect, the therapeutic agent is Camptothecin, or an analog or derivative thereof. Camptothecins have the following general structure.

[0059]

In this structure, X is typically O, but can be other groups, e.g., NH in the case of 21-lactam derivatives. R1 is typically H or OH, but may be other groups, e.g., a terminally hydroxylated C1-3 alkane. R2 is typically H or an amino containing group such as (CH3)2NHCH2, but may be other groups e.g., NO2; NH2, halogen (as disclosed in, e.g., U.S. Pat. No. 5,552,156) or a short alkane containing these groups. R3 is typically H or a short alkyl such as C2H5. R4 is typically H but may be other groups, e.g., a methylenedioxy group with R1.

and R2 is an alkyl group having 1-4 carbons and R3 is one of H, acyl, methyl, ethyl, and mixtures thereof, such as a methylether.

[0066]

Other suitable hydroxyureas are disclosed in. e.g., U.S. Pat. No. 5,665,768, wherein R1 is a cycloalkenyl group, for example N-[3-[5-(4-fluorophenylthio)-furyl]-2-cyclopenten-1-yl]N-hydroxyurea; R2 is H or an alkyl group having 1 to 4 carbons and R3 is H; X is H or a cation.

[0067]

Other suitable hydroxyureas are disclosed in, e.g., U.S. Pat. No. 4,299,778, wherein R1 is a phenyl group substituted with one or more fluorine atoms; R2 is a cyclopropyl group; and R3 and X is H.

[0068]

Other suitable hydroxyureas are disclosed in, e.g., U.S. Pat. No. 5,066,658, wherein R2 and R3 together with the adjacent nitrogen form:

[0069]

wherein m is 1 or 2, n is 0-2 and Y is an alkyl group.

[0070]

In one aspect, the hydroxyurea has the structure:

[0071]

These compounds are thought to function by inhibiting DNA synthesis.

G. Platinum Complexes

[0072]

In another aspect, the therapeutic agent is a platinum compound. In general, suitable platinum complexes may be of Pt(lI) or Pt(IV) and have this basic structure:

[0073]

wherein X and Y are anionic leaving groups such as sulfate, phosphate, carboxylate, and halogen; R1 and R2 are alkyl, amine, amino alkyl any may be further substituted, and are basically inert or bridging groups. For Pt(II) complexes Z1 and Z2 are non-existent. For Pt(IV) Z1 and Z2 may be anionic groups such as halogen, hydroxy, carboxylate, ester, sulfate or phosphate. See, e.g., U.S. Pat. Nos. 4,588,831 and 4,250,189.

As noted above, therapeutic agents described herein may be formulated in a variety of manners, and thus may additionally comprise a carrier. In this regard, a wide variety of carriers may be selected of either polymeric or non-polymeric origin. The polymers and non-polymer based carriers and formulations which are discussed in more detail below are provided merely by way of example, not by way of limitation.

Representative examples of thermogelling polymers include homopolymers such as poly(N-methyl-N-n-propylacrylamide), poly(N-n-propylacrylamide), poly(N-methyl-N-isopropylacrylamide), poly(N-n-propylmethacrylamide), poly(N-isopropylacrylamide), poly(N,n-diethylacrylamide), poly(N-isopropylmethacrylamide), poly(N-cyclopropylacrylam ide), poly(N-ethylmethyacrylamide), poly(N-methyl-N-ethylacrylam ide), poly(N-cyclopropylmethacrylamide) and poly(N-ethylacrylamide). Moreover thermogelling polymers may be made by preparing copolymers between (among) monomers of the above, or by combining such homopolymers with other water soluble polymers such as acrylmonomers (e.g., acrylic acid and derivatives thereof such as methylacrylic acid, acrylate and derivatives thereof such as butyl methacrylate, acrylamide, and N-n-butyl acrylamide).

[0084]

Other representative examples of thermogelling cellulose ether derivatives such as hydroxypropyl cellulose, methyl cellulose, hydroxypropylmethyl cellulose, ethylhydroxyethyl cellulose, and Pluronics, such as F-127.

Preferably, therapeutic compositions of the present invention are fashioned in a manner appropriate to the intended use. Within certain aspects of the present invention, the therapeutic composition should be biocompatible, and release one or more agents over a period of several days to months. Further, therapeutic compositions of the present invention should preferably be stable for several months and capable of being produced, and maintained under sterile conditions.

[0088]

Within certain aspects of the present invention, therapeutic compositions may be fashioned in any size ranging from 50 nm to 500 μm, depending upon the particular use. Alternatively, such compositions may also be readily applied as a “spray” which solidifies into a film or coating. Such sprays may be prepared from microspheres of a wide array of sizes, including for example, from 0.1 μm to 9 μm, from 10 μm to 30 μm and from 30 μm to 100 μm.

[0089]

Therapeutic compositions of the present invention may also be prepared in a variety of “paste” or gel forms. For example, within one embodiment of the invention, therapeutic compositions are provided which are liquid at one temperature (e.g., temperature greater than 37° C.) and solid or semi-solid at another temperature (e.g., ambient body temperature, or any temperature lower than 37° C.). Also included are polymers, such as Pluronic F-127, which are liquid at a low temperature (e.g., 4° C.) and a gel at body temperature. Such “thermopastes” may be readily made given the disclosure provided herein.

[0090]

Within yet other aspects of the invention, the therapeutic compositions of the present invention may be formed as a film. Preferably, such films are generally less than 5, 4, 3, 2 or 1 mm thick, more preferably less than 0.75 mm or 0.5 mm thick, and most preferably less than 500 μm. Such films are preferably flexible with a good tensile strength (e.g., greater than 50, preferably greater than 100, and more preferably greater than 150 or 200 N/cm2), good adhesive properties (i.e., readily adheres to moist or wet surfaces), and have controlled permeability.

[0091]

Within certain embodiments of the invention, the therapeutic compositions can also comprise additional ingredients such as surfactants (e.g., Pluronics such as F-127, L-122, L-92, L-81, and L-61).

[0092]

Within further aspects of the present invention, polymers are provided which are adapted to contain and release a hydrophobic compound, the carrier containing the hydrophobic compound in combination with a carbohydrate, protein or polypeptide. Within certain embodiments, the polymeric carrier contains or comprises regions, pockets or granules of one or more hydrophobic compounds. For example, within one embodiment of the invention, hydrophobic compounds may be incorporated within a matrix which contains the hydrophobic compound, followed by incorporation of the matrix within the polymeric carrier. A variety of matrices can be utilized in this regard, including for example, carbohydrates and polysaccharides, such as starch, cellulose, dextran, methylcellulose, and hyaluronic acid, proteins or polypeptides such as albumin, collagen and gelatin. Within alternative embodiments, hydrophobic compounds may be contained within a hydrophobic core, and this core contained within a hydrophilic shell.

The agents provided herein can also be formulated as a sterile composition (e.g., by treating the composition with ethylene oxide or by irradiation), packaged with preservatives or other suitable excipients suitable for administration to humans. Similarly, the devices provided herein (e.g., coated catheter) may be sterilized and prepared suitable for implantation into humans.

Implants and other surgical or medical devices may be covered, coated, contacted, combined, loaded, filled, associated with, or otherwise adapted to release therapeutic agents compositions of the present invention in a variety of manners, including for example: (a) by directly affixing to the implant or device a therapeutic agent or composition (e.g., by either spraying the implant or device with a polymer/drug film, or by dipping the implant or device into a polymer/drug solution, or by other covalent or noncovalent means); (b) by coating the implant or device with a substance, such as a hydrogel, which will in turn absorb the therapeutic composition (or therapeutic factor above); (c) by interweaving therapeutic composition coated thread (or the polymer itself formed into a thread) into the implant or device; (d) by inserting the implant or device into a sleeve or mesh which is comprised of or coated with a therapeutic composition; (e) constructing the implant or device itself with a therapeutic agent or composition; or (f) by otherwise adapting the implant or device to release the therapeutic agent. Within preferred embodiments of the invention, the composition should firmly adhere to the implant or device during storage and at the time of insertion. The therapeutic agent or composition should also preferably not degrade during storage, prior to insertion, or when warmed to body temperature after insertion inside the body (if this is required). In addition, it should preferably coat or cover the desired areas of the implant or device smoothly and evenly, with a uniform distribution of therapeutic agent. Within preferred embodiments of the invention, the therapeutic agent or composition should provide a uniform, predictable, prolonged release of the therapeutic factor into the tissue surrounding the implant or device once it has been deployed. For vascular stents, in addition to the above properties, the composition should not render the stent thrombogenic (causing blood clots to form), or cause significant turbulence in blood flow (more than the stent itself would be expected to cause if it was uncoated).

[0097]

Within certain embodiments of the invention, a therapeutic agent can be deposited directly onto all or a portion of the device (see, e.g., U.S. Pat. Nos. 6,096,070 and 6,299,604), or admixed with a delivery system or carrier (e.g., a polymer, liposome, or vitamin as discussed above) which is applied to all or a portion of the device (see the patents, patent applications, and references listed above under “Compositions and Formulations.”

[0098]

Within certain aspects of the invention, therapeutic agents can be attached to a medical implant using non-covalent attachments. For example, for compounds that are relatively sparingly water soluble or water insoluble, the compound can be dissolved in an organic solvent a specified concentration. The solvent chosen for this application would not result in dissolution or swelling of the polymeric device surface. The medical implant can then be dipped into the solution, withdrawn and then dried (air dry and/or vacuum dry). Alternatively, this drug solution can be sprayed onto the surface of the implant. This can be accomplished using current spray coating technology. The release duration for this method of coating would be relatively short and would be a function of the solubility of the drug in the body fluid in which it was placed.

[0099]

In another aspect, a therapeutic agent can be dissolved in a solvent that has the ability to swell or partially dissolve the surface of a polymeric implant. Depending on the solvent/implant polymer combination, the implant could be dipped into the drug solution for a period of time such that the drug can diffuse into the surface layer of the polymeric device. Alternatively the drug solution can be sprayed onto all or a part of the surface of the implant. The release profile of the drug depends upon the solubility of the drug in the surface polymeric layer. Using this approach, one would ensure that the solvent does not result in a significant distortion or dimensional change of the medical implant.

[0100]

If the implant is composed of materials that do not allow incorporation of a therapeutic agent into the surface layer using the above solvent method, one can treat the surface of the device with a plasma polymerization method such that a thin polymeric layer is deposited onto the device surface. Examples of such methods include parylene coating of devices, and the use of various monomers such hydrocyclosiloxane monomers, acrylic acid, acrylate monomers, methacrylic acid or methacrylate monomers. One can then use the dip coating or spray coating methods described above to incorporate the therapeutic agent into the coated surface of the implant.

[0101]

For therapeutic agents that have some degree of water solubility, the retention of these compounds on a device are relatively short-term. For therapeutic agents that contain ionic groups, it is possible to tonically complex these agents to oppositely charged compounds that have a hydrophobic component. For example therapeutic agents containing amine groups can be complexed with compounds such as sodium dodecyl sulfate (SDS). Compounds containing carboxylic groups can be complexed with tridodecymethyammonium chloride (TDMAC). Mitoxantrone, for example, has two secondary amine groups and comes as a chloride salt. This compound can be added to sodium dodecyl sulfate in order to form a complex. This complex can be dissolved in an organic solvent which can then be dip coated or spray coated. Doxorubicin has an amine group and could thus also be complexed with SDS. This complex could then be applied to the device by dip coating or spray coating methods. Methotrexate, for example contains 2 carboxylic acid groups and could thus be complexed with TDMAC and then coated onto the medical implant.

[0102]

For therapeutic agents that have the ability to form ionic complexes or hydrogen bonds, the release of these agents from the device can be modified by the use of organic compounds that have the ability to form ionic or hydrogen bonds with the therapeutic agent. As described above, a complex between the ionically charged therapeutic agent and an oppositely charged hydrophobic compound can be prepared prior to application of this complex to the medical implant. In another embodiment, a compound that has the ability to form ionic or hydrogen bond interactions with the therapeutic agent can be incorporated into the implant during the manufacture process, or during the coating process. Alternatively, this compound can be incorporated into a coating polymer that is applied to the implant or during the process of loading the therapeutic agent into or onto the implant. These agents can include fatty acids (e.g., palmitic acid, stearic acid, lauric acid), aliphatic acids, aromatic acids (e.g., benzoic acid, salicylic acid), cylcoaliphatic acids, aliphatic (stearyl alcohol, lauryl alcohol, cetyl alcohol) and aromatic alcohols alco multifunctional alcohols (e.g., citric acid, tartaric acid, pentaerithratol), lipids (e.g., phosphatidyl choline, phosphatidylethanolamine), carbohydrates, sugars, spermine, spermidine, aliphatic and aromatic amines, natural and synthetic amino acids, peptides or proteins. For example, a fatty acid such as palmitic acid can be used to modulate the release of 5-Fluoruracil from the implant.

[0103]

For therapeutic agents that have the ability to form ionic complexes or hydrogen bonds, the release of these agents from the implant can be modified by the use of polymers that have the ability to form ionic or hydrogen bonds with the therapeutic agent. For example, therapeutic agents containing amine groups can form ionic complexes with sulfonic or carboxylic pendant groups or end-groups of a polymer. Examples of polymers that can be used for this application include, but are not limited to polymers and copolymers that are prepared using acrylic acid, methacrylic acid, sodium styrene sulfonate, styrene sulfonic acid, maleic acid or 2-acrylamido-2-methyl propane sulfonic acid. Polymers that have been modified by sulfonation post-polymerization can also be used in this application. The medical implant, for example, can be coated with, or prepared with, a polymer that comprises nafion, a sulfonated fluoropolymer. This medical device can then be dipped into a solution that comprises the amine-containing therapeutic agent. The amine-containing therapeutic agent can also be applied by a spray coating process. Methotrexate and doxorubicin are examples of therapeutic agents that can be used in this application.

[0104]

It is known that the presence of bacteria on the implant surface can result in a localized decrease in pH. For polymers that comprise ionic exchange groups, for example, carboxylic groups, these polymers can have a localized increase in release of the therapeutic agent in response to the localized decrease in pH as a result of the presence of the bacteria. For therapeutic agents that contain carboxylic acid groups, polymers with pendant end-groups comprising primary, secondary, tertiary or quaternary amines can be used to modulate the release of the therapeutic agent.

[0105]

Therapeutic agents with available functional groups can be covalently attached to the medical implant surface using several chemical methods. If the polymeric material used to manufacture the implant has available surface functional groups then these can be used for covalent attachment of the agent. For example, if the implant surface contains carboxylic acid groups, these groups can be converted to activated carboxylic acid groups (e.g acid chlorides, succinimidyl derivatives, 4-nitrophenyl ester derivatives etc). These activated carboxylic acid groups can then be reacted with amine functional groups that are present on the therapeutic agent (e.g., methotrexate, mitoxantrone).

[0106]

For surfaces that do not contain appropriate functional groups, these groups can be introduced to the polymer surface via a plasma treatment regime. For example, carboxylic acid groups can be introduced via a plasma treatment process process (e.g., the use of O2 and/or CO2 as a component in the feed gas mixture). The carboxylic acid groups can also be introduced using acrylic acid or methacrylic acid in the gas stream. These carboxylic acid groups can then be converted to activated carboxylic acid groups (e;g., acid chlorides, succinimidyl derivatives, 4-nitrophenyl ester derivatives, etc.) that can subsequently be reacted with amine functional groups that are present on the therapeutic agent.

[0107]

In addition to direct covalent bonding to the implant surface, the therapeutic agents with available functional groups can be covalently attached to the medical implant via a linker. These linkers can be degradable or non-degradable. Linkers that are hydrolytically or enzymatically cleaved are preferred. These linkers can comprise azo, ester, amide, thioester, anhydride, or phosphoester bonds.

[0108]

To further modulate the release of the therapeutic agent from the medical implant, portions of or the entire medical implant may be further coated with a polymer. The polymer coating can comprise the polymers described above. The polymer coating can be applied by a dip coating process, a spray coating process or a plasma deposition process. This coating can, if desired, be further crosslinked using thermal, chemical, or radiation (e.g., visible light, ultraviolet light, e-beam, gamma radiation, x-ray radiation) techniques in order to further modulate the release of the therapeutic agent from the medical implant.

[0109]

This polymer coating can further contain agents that can increase the flexibility (e.g., plasticizer—glycerol, triethyl citrate), lubricity (e.g., hyaluronic acid), biocompatibility or hemocompatability,(e.g., heparin) of the coating.

In order to further the understanding of the invention, discussed in more detail below are various clinical applications for the compositions, methods and devices provided herein.

[0112]

Briefly, as noted above, within one aspect of the invention methods are provided for preventing, reducing, and/or inhibiting an infection associated with a medical device or implant, comprising the step of introducing into a patient a medical implant which releases a chemotherapeutic agent, wherein the chemotherapeutic agent reduces, inhibits, or prevents the growth or transmission of foreign organisms (e.g., bacteria, fungi, or viruses). As used herein, agents that reduce, inhibit, or prevent the growth or transmission of foreign organisms in a patient means that the growth or transmission of a foreign organism is reduced, inhibited, or prevented in a statistically significant manner in at least one clinical outcome, or by any measure routinely used by persons of ordinary skill in the art as a diagnostic criterion in determining the same. In a preferred embodiment, the medical implant has been covered or coated with an anthracycline (e.g., doxorubicin and mitoxantrone), fluoropyrimidine (e.g., 5-FU), folic acid antagonist (e.g., methotrexate), podophylotoxin (e.g., etoposide), camptothecin, hydroxyurea, and/or a platinum complexe (e.g., cisplatin).

[0113]

Particularly preferred agents which are utilized within the context of the present invention should have an MIC of less than or equal to any one of 10−4M, 10−5M, 10−6M, or, 10−7M. Furthermore, particularly preferred agents are suitable for use at concentrations less than that 10%, 5%, or even 1% of the concentration-typically used in chemotherapeutic applications (Goodman and Gilman's The Pharmacological Basis of Therapeutics. Editors J. G. Hardman, L. L. Limbird. Consulting editor A. Goodman Gilman Tenth Edition. McGraw-Hill Medical publishing division. 10th edition, 2001, 2148 pp.). Finally, the devices should preferably be provided sterile, and suitable for use in humans.

Unfortunately, vascular access catheters are prone to infection by a variety of bacteria and are a common cause of bloodstream infection. Of the 100,000 bloodstream infections in US hospitals each year, many are related to the presence of an intravascular device. For example, 55,000 cases of bloodstream infections are caused by central venous catheters, while a significant percentage of the remaining cases are related to peripheral intravenous catheters and arterial lines.

[0116]

Bacteremia related to the presence of intravascular devices is not a trivial clinical concern: 50% of all patients developing this type of infection will die as a result (over 23,000 deaths per year) and in those who survive, their hospitalization will be prolonged by an average of 24 days. Complications related to bloodstream infections include cellulites, the formation of abscesses, septic thrombophlebitis, and infective endocarditis. Therefore, there is a tremendous clinical need to reduce the morbidity and mortality associated with intravascular catheter infections.

[0117]

The most common point of entry for the infection-causing bacteria is tracking along the device from the insertion site in the skin. Skin flora spread along the outside of the device to ultimately gain access to the bloodstream. Other possible sources of infection include a contaminated infusate, contamination of the catheter hub-infusion tubing junction, and hospital personnel. The incidence of infection increases the longer the catheter remains in place and any device remaining in situ for more than 72 hours is particularly susceptible. The most common infectious agents include common skin flora such as coagulase-negative staphylococci (S. epidermidis, S. saprophyticus) and Staphylococcus aureus (particularly MRSA—methicillin—resistant S. aureus) which account for ⅔ of all infections. Coagulase-negative staphylococci (CNS) is the most commonly isolated organism from the blood of hospitalized patients. CNS infections tend to be indolent; often occurring after a long latent period between contamination (i.e. exposure of the medical device to CNS bacteria from the skin during implantation) and the onset of clinical illness. Unfortunately, most clinically significant CNS infections are caused by bacterial strains that are resistant to multiple antibiotics, making them particularly difficult to treat. Other organisms known to cause vascular access catheter-related infections include Enterococci (e.g. E. coli, VRE—vancomycin-resistant enterococcci), Gram-negative aerobic bacilli, Pseudomonas aeruginosa, Klebsiella spp., Serratia marcescens, Burkholderia cepacia, Citrobacter freundii, Corynebacteria spp. and Candida species.

[0118]

Most cases of vascular access catheter-related infection require removal of the catheter and treatment with systemic antibiotics (although few antibiotics are effective), with vancomycin being the drug of choice. As mentioned previously, mortality associated with vascular access catheter-related infection is high, while the morbidity and cost associated with treating survivors is also extremely significant.

[0119]

It is therefore extremely important to develop vascular access catheters capable of reducing the incidence of bloodstream infections. Since it is impossible to predict in advance which catheters will become infected, any catheter expected to be in place longer than a couple of days would benefit from a therapeutic coating capable of reducing the incidence of bacterial colonization of the device. An ideal therapeutic coating would have one or more of the following characteristics: (a) the ability to kill, prevent, or inhibit colonization of a wide array of potential infectious agents including most or all of the species listed above; (b) the ability to kill, prevent, or inhibit colonization of bacteria (such as CNS and VRE) that are resistant to multiple antibiotics; (c) utilize a therapeutic agent unlikely to be used in the treatment of a bloodstream infection should one develop (i.e., one would not want to coat the device with a broad-acting antibiotic, for if a strain of bacteria resistant to the antibiotic were to develop on the device it would jeopardize systemic treatment of the patient since the infecting agent would be resistant to a potentially useful therapeutic).

[0120]

Several classes of anticancer agents are particularly suitable for incorporation into coatings for vascular catheters, namely, anthracyclines (e.g., doxorubicin and mitoxantrone), fluoropyrimidines (e.g., 5-FU), folic acid antagonists (e.g., methotrexate), and podophylotoxins (e.g., etoposide). These agents have a high degree of antibacterial activity against CNS (S. epidermidis) and Staphylococcus aureus—the most common causes of vascular catheter infections. Particularly preferred agents are doxorubicin, mitoxantrone, 5-fluorouracil and analogues and derivatives thereof which also have activity against Escheridia coli and Pseudomonas aeruginosa. It is important to note that not all anticancer agents are suitable for the practice of the present invention as several agents, including 2-mercaptopurine, 6-mercaptopurine, hydroxyurea, cytarabine, cisplatinum, tubercidin, paclitaxel, and camptothecin did not have antibacterial activity against the organisms known to cause vascular access catheter-related infections.

[0121]

1. Central Venous Catheters

[0122]

For the purposes of this invention, the term “Central Venous Catheters” should be understood to include any catheter or line that is used to deliver fluids to the large (central) veins of the body (e.g., jugular, pulmary, femoral, iliac, inferior vena cava, superior vena cava, axillary etc.). Examples of such catheters include central venous catheters, total parenteral nutrition catheters, peripherally inserted central venous catheters, flow-directed balloon-tipped pulmonary artery catheters, long-term central venous access catheters (such as Hickman lines and Broviac catheters). Representative examples of such catheters are described in U.S. Pat. Nos. 3,995,623, 4,072,146 4,096,860, 4,099,528, 4,134,402, 4,180,068, 4,385,631, 4,406,656, 4.568,329, 4,960,409, 5,176,661, 5,916,208.

[0123]

As described previously, 55,000 cases of bloodstream infections are caused by central venous catheters every year in the United States resulting in 23,000 deaths. The risk of infection increases the longer the catheter remains in place, particularly if it is used beyond 72 hours. Severe complications of central venous catheter infection also include infective endocarditis and suppurative phlebitis of the great veins. If the device becomes infected, it must be replaced at a new site (over-the-wire exchange is not acceptable) which puts the patient at further risk to develop mechanical complications of insertion such as bleeding, pneumothorax and hemothorax. In addition, systemic antibiotic therapy is also required. An effective therapy would reduce the incidence of device infection, reduce the incidence of bloodstream infection, reduce the mortality rate, reduce the incidence of complications (such as endocarditis or suppurative phlebitis), prolong the effectiveness of the central venous catheter and/or reduce the need to replace the catheter. This would result in lower mortality and morbidity for patients with central venous catheters in place.

[0124]

In a preferred embodiment, doxorubicin, mitoxantrone, 5-fluorouracil and/or etoposide are formulated into a coating applied to the surface of the vascular catheter. The drug(s) can be applied to the central venous catheter system in several manners: (a) as a coating applied to the exterior surface of the intravascular portion of the catheter and/or the segment of the catheter that traverses the skin; (b) as a coating applied to the interior and exterior surface of the intravascular portion of the catheter and/or the segment of the catheter that traverses the skin; (c) incorporated into the polymers which comprise the intravascular portion of the catheter; (d) incorporated into, or applied to the surface of, a subcutaneous “cuff” around the catheter; (e) in solution in the infusate; (e incorporated into, or applied as a coating to, the catheter hub, junctions and/or infusion tubing; and (g) any combination of the aforementioned.

[0125]

Drug-coating of, or drug incorporation into, the central venous catheter will allow bacteriocidal drug levels to be achieved locally on the catheter surface, thus reducing the incidence of bacterial colonization of the vascular catheter (and subsequent development of blood borne infection), while producing negligible systemic exposure to the drugs. Although for some agents polymeric carriers are not required for attachment of the drug to the catheter surface, several polymeric carriers are particularly suitable for use in this embodiment. Of particular interest are polymeric carriers such as polyurethanes (e.g., ChronoFlex AL 85A [CT Biomaterials], HydroMed640™ [CT Biomaterials], HYDROSLIP C™ [CT Biomaterials], HYDROTHANE™ [CT Biomaterials]), acrylic or methacrylic copolymers (e.g., poly(ethylene-co-acrylic acid), cellulose-derived polymers (e.g. nitrocellulose, Cellulose Acetate Butyrate, Cellulose acetate propionate), acrylate and methacrylate copolymers (e.g., poly(ethylene-co-vinyl acetate)) as well as blends thereof.

[0126]

As central venous catheters are made in a variety of configurations and sizes, the exact dose administered will vary with device size, surface area and design. However, certain principles can be applied in the application of this art. Drug dose can be calculated as a function of dose per unit area (of the portion of the device being coated), total drug dose administered can be measured and appropriate surface concentrations of active drug can be determined. Regardless of the method of application of the drug to the central venous catheter, the preferred anticancer agents, used alone or in combination, should be administered under the following dosing guidelines:

[0127]

(a) Anthracyclines. Utilizing the anthracycline doxorubicin as an example, whether applied as a polymer coating, incorporated into the polymers which make up the device, or applied without a polymer carrier, the total dose of doxorubicin applied to the central venous catheter (and the other components of the infusion system) should not exceed 25 mg (range of 0.1 μg to 25 mg). In a particularly preferred embodiment, the total amount of drug applied to the central venous catheter (and the other components of the infusion system) should be in the range of 1 μg to 5 mg. The dose per unit area of the device (i.e. the amount of drug as a function of the surface area of the portion of the device to which drug is applied and/or incorporated) should fall within the range of 0.01 μg-100 μg per mm2 of surface area. In a particularly preferred embodiment, doxorubicin should be applied to the device surface at a dose of 0.1 μg/mm2-10 μg/mm2. As different polymer and non-polymer coatings will release doxorubicin at differing rates, the above dosing parameters should be utilized in combination with the release rate of the drug from the device surface such that a minimum concentration of 10−7-10−4 M of doxorubicin is maintained on the device surface. It is necessary to insure that drug concentrations on the device surface exceed concentrations of doxorubicin known to be lethal to multiple species of bacteria and fungi (i.e., are in excess of 10−4 M; although for some embodiments lower concentrations are sufficient). In a preferred embodiment, doxorubicin is released from the surface of the device such that anti-infective activity is maintained for a period ranging from several hours to several months. In a particularly preferred embodiment the drug is released in effective concentrations for a period ranging from 1-30 days. It should be readily evident given the discussions provided herein that analogues and derivatives.of doxorubicin (as described previously) with similar functional activity can be utilized for the purposes of this invention; the above dosing parameters are then adjusted according to the relative potency of the analogue or derivative as compared to the parent compound (e.g. a compound twice as potent as doxorubicin is administered at half the above parameters, a compound half as potent as doxorubicin is administered at twice the above parameters, etc.).

[0128]

Utilizing mitoxantrone as another example of an anthracycline, whether applied as a polymer coating, incorporated into the polymers which make up the device, or applied without a carrier polymer, the total dose of mitoxantrone applied to the central venous catheter (and the other components of the infusion system) should not exceed 5 mg (range of 0.01 μg to 5 mg). In a particularly preferred embodiment, the total amount of drug applied to the central venous catheter (and the other components of the infusion system) should be in the range of 0.1 μg to 1 mg. The dose per unit area of the device (i.e. the amount of drug as a function of the surface area of the portion of the device to which drug is applied and/or incorporated) should fall within the range of 0.01 μg-20 μg per mm2 of surface area. In a particularly preferred embodiment, mitoxantrone should be applied to the device surface at a dose of 0.05 μg/mm2-3 μg/mm2. As different polymer and non-polymer coatings will release mitoxantrone at differing rates, the above dosing parameters should be utilized in combination with the release rate of the drug from the device surface such that a minimum concentration of 10−5-10−6 M of mitoxantrone is maintained on the device surface. It is necessary to insure that drug concentrations on the device surface exceed concentrations of mitoxantrone known to be lethal to multiple species of bacteria and fungi (i.e. are in excess of 10−5 M; although for some embodiments lower drug levels will be sufficient). In a preferred embodiment, mitoxantrone is released from the surface of the device such that anti-infective activity is maintained for a period ranging from several hours to several months. In a particularly preferred embodiment the drug is released in effective concentrations for a period ranging from 1-30 days. It should be readily evident given the discussions provided herein that analogues and derivatives of mitoxantrone (as described previously) with similar functional activity can be utilized for the purposes of this invention; the above dosing parameters are then adjusted according to the relative potency of the analogue or derivative as compared to the parent compound (e.g. a compound twice as potent as mitoxantrone is administered at half the above parameters, a compound half as potent as mitoxantrone is administered at twice the above parameters, etc.).

[0129]

(b) Fluoropyrimidines Utilizing the fluoropyrimidine 5-fluorouracil as an example, whether applied as a polymer coating, incorporated into the polymers which make up the device, or applied without a carrier polymer, the total dose of 5-fluorouracil applied to the central venous catheter (and the other components of the infusion system) should not exceed 250 mg (range of 1.0 μg to 250 mg). In a particularly preferred embodiment, the total amount of drug applied to the central venous catheter (and the other components of the infusion system) should be in the range of 10 μg to 25 mg. The dose per unit area of the device (i.e. the amount of drug as a function of the surface area of the portion of the device to which drug is applied and/or incorporated) should fall within the range of 0.1 μg-1 mg per mm2 of surface area. In a particularly preferred embodiment, 5-fluorouracil should be applied to the device surface at a dose of 1.0 μg/mm2-50 μg/mm2. As different polymer and non-polymer coatings will release 5-fluorouracil at differing rates, the above dosing parameters should be utilized in combination with the release rate of the drug from the device surface such that a minimum concentration of 10−4-10−7 M of 5-fluorouracil is maintained on the device surface. It is necessary to insure that drug concentrations on the device surface exceed concentrations of 5-fluorouracil known to be lethal to numerous species of bacteria and fungi (i.e., are in excess of 10−4 M; although for some embodiments lower drug levels will be sufficient). In a preferred embodiment, 5-fluorouracil is released from the surface of the device such that anti-infective activity is maintained for a period ranging from several hours to several months. In a particularly preferred embodiment the drug is released in effective concentrations for a period ranging from 1-30 days. It should be readily evident given the discussions provided herein that analogues and derivatives of 5-fluorouracil (as described previously) with similar functional activity can be utilized for the purposes of this invention; the above dosing parameters are then adjusted according to the relative potency of the analogue or derivative as compared to the parent compound (e.g. a compound twice as potent as 5-fluorouracil is administered at half the above parameters, a compound half as potent as 5-fluorouracil is administered at twice the above parameters, etc.).

[0130]

(c) Podophylotoxins Utilizing the podophylotoxin etoposide as an example, whether applied as a polymer coating, incorporated into the polymers which make up the device, or applied without a carrier polymer, the total dose of etoposide applied to the central venous catheter (and the other components of the infusion system) should not exceed 25 mg (range of 0.1 μg to 25 mg). In a particularly preferred embodiment, the total amount of drug applied to the central venous catheter (and the other components of the infusion system) should be in the range of 1 μg to 5 mg. The dose per unit area of the device (i.e. the amount of drug as a function of the surface area of the portion of the device to which drug is applied and/or incorporated) should fall within the range of 0.01 μg-100 μg per mm2 of surface area. In a particularly preferred embodiment, etoposide should be applied to the device surface at a dose of 0.1 μg/mm2-10 μg/mm2. As different polymer and non-polymer coatings will release etoposide at differing rates, the above dosing parameters should be utilized in combination with the release rate of the drug from the device surface such that a concentration of 10−5-10−6 M of etoposide is maintained on the device surface. It is necessary to insure that drug concentrations on the device surface exceed concentrations of etoposide known to be lethal to a variety of bacteria and fungi (i.e., are in excess of 10−5 M; although for some embodiments lower drug levels will be sufficient). In a preferred embodiment, etoposide is released from the surface of the device such that anti-infective activity is maintained for a period ranging from several hours to several months. In a particularly preferred embodiment the drug is released in effective concentrations for a period ranging from 1-30 days. It should be readily evident based upon the discussions provided herein that analogues and derivatives of etoposide (as described previously) with similar functional activity can be utilized for the purposes of this invention; the above dosing parameters are then adjusted according to the relative potency of the analogue or derivative as compared to the parent compound (e.g. a compound twice as potent as etoposide is administered at half the above parameters, a compound half as potent as etoposide is administered at twice the above parameters, etc.).

For the purposes of this invention, the term “Peripheral Venous Catheters” should be understood to include any catheter or line that is used to deliver fluids to the smaller (peripheral) superficial veins of the body.

[0134]

Peripheral venous catheters have a much lower rate of infection than do central venous catheters, particularly if they are in place for less than 72 hours. One exception is peripheral catheters inserted into the femoral vein (so called “femoral lines”) which have a significantly higher rate of infection. The organisms that cause infections in a peripheral venous catheter are identical to those described above (for central venous catheters).

[0135]

In a preferred embodiment, doxorubicin, mitoxantrone, 5-fluorouracil and/or etoposide are formulated into a coating applied to the surface of the peripheral vascular catheter. The drug(s) can be applied to the peripheral venous catheter system in several manners: (a) as a coating applied to the exterior and/or interior surface of the intravascular portion of the catheter and/or the segment of the catheter that traverses the skin; (b) incorporated into the polymers which comprise the intravascular portion of the catheter; (c) incorporated into, or applied to the surface of, a subcutaneous “cuff” around the catheter; (e) in solution in the infusate; (f incorporated into, or applied as a coating to, the catheter hub, junctions and/or infusion tubing; and (g) any combination of the aforementioned.

[0136]

The formulation and dosing guidelines for this embodiment are identical to those described for central venous catheters.

[0137]

3. Arterial Lines and Transducers

[0138]

Arterial lines are used to draw arterial blood gasses, obtain accurate blood pressure readings and to deliver fluids. They are placed in a peripheral artery (typically the radial artery) and often remain in place for several days. Arterial lines have a very high rate of infection (12-20% of arterial lines become infected) and the causative organisms are identical to those described above (for central venous catheters).

[0139]

In a preferred embodiment, doxorubicin, mitoxantrone, 5-fluorouracil and/or etoposide are formulated into a coating applied to the arterial line in several manners: (a) as a coating applied to the exterior and/or interior surface of the intravascular portion of the catheter and/or the segment of the catheter that traverses the skin; (b) incorporated into the polymers which comprise the intravascular portion of the catheter; (c) incorporated into, or applied to the surface of, a subcutaneous “cuff” around the catheter; (e) in solution in the infusate; (f) incorporated into, or applied as a coating to, the catheter hub, junctions and/or infusion tubing; and (g) any combination of the aforementioned.

[0140]

The formulation and dosing guidelines for this embodiment are identical to those described for central venous catheters.

B. Prosthetic Heart Valve Endocarditis (PVE)

[0141]

Prosthetic heart valves, mechanical and bioprosthetic, are at a significant risk for developing an infection. In fact, 3-6% of patients develop valvular infection within 5 years of valve replacement surgery and prosthetic valve endocarditis accounts for up to 15% of all cases of endocarditis. The risk of developing an infection is not uniform—the risk is greatest in the first year following surgery with a peak incidence between the second and third month postoperatively. Mechanical valves in particular are susceptible to infection in the 3 months following surgery and the microbiology is suggestive of nosocomial infection. Therefore, a drug coating designed to prevent colonization and infection of the valves in the months following surgery could be of great benefit in the prevention of this important medical problem. The incidence of prosthetic valve endocarditis has not changed in the last 40 years despite significant advances in surgical and sterilization technique.

[0142]

Representative examples of prosthetic heart valves include those described in U.S. Pat. Nos. 3,656,185, 4,106,129, 4,892,540, 5,528,023, 5,772,694, 6,096,075, 6,176,877, 6,358,278, and 6,371,983

[0143]

Early after valve implantation, the prosthetic valve sewing ring and annulus are not yet endothelialized. The accumulation of platelets and thrombus at the site provide an excellent location for the adherence and colonization of microorganisms. Bacteria can be seeded during the surgical procedure itself or as a result of bacteremia arising in the early postoperative period (usually contamination from i.v. catheters, catheters to determine cardiac output, mediastinal tubes, chest tubes or wound infections). Common causes of PVE include Coagulase Negative Staphylococci (Staphylococcus epidermidis; 30%), Staphylococcus aureus (23%), Gram Negative Enterococci (Enterobacteriaceae, Pseudomonas arugenosa; 14%), Fungi (Candida albicans, Aspergillis: 12%), and Corynebacterium diptheriae. PVE of bioprosthetic valves is largely confined to the leaflets (and rarely the annulus), whereas the annulus is involved in the majority of cases of PVE in mechanical valves (82%).

[0144]

Unfortunately, eradication of the infecting organism with antimicrobial therapy alone is often difficult or impossible. As a result, many patients who develop this complication require repeat open-heart surgery to replace the infected valve resulting in significant morbidity and mortality. Even if the infection is successfully treated medically, damage to the leaflets in bioprosthetic valves reduces the lifespan of the valve. Particularly problematic are patients who develop an infection caused by Staphylococcus aureus, as they have a 50-85% mortality rate and overall reoperation rate of 50-65%. Infections caused by Staphylococcus epidermidis are also difficult to treat as the majority are caused by organisms resistant to all currently available beta-lactam antibiotics. Other complications of prosthetic valve endocarditis include valve malfunction (stenosis, regurgitation), abscess formation, embolic complications (such as stroke, CNS hemorrhage, cerebritis), conduction abnormalities, and death (55-75% of patients who develop an infection in the first 2 months after surgery).

[0145]

An effective therapeutic valve coating would reduce the incidence of prosthetic valve endocarditis, reduce the mortality rate, reduce the incidence of complications, prolong the effectiveness of the prosthetic valve and/or reduce the need to replace the valve. This would result in lower mortality and morbidity for patients with prosthetic heart valves.

[0146]

In a preferred embodiment, doxorubicin, mitoxantrone, 5-fluorouracil and/or etoposide are formulated into a coating applied to the surface of the bioprosthetic or mechanical valve. The drug(s) can be applied to the prosthetic valve in several manners: (a) as a coating applied to the surface of the annular ring (particularly mechanical valves); (b) as a coating applied to the surface of the valve leaflets (particularly bioprosthetic valves); (c) incorporated into the polymers which comprise the annular ring; and/or (d) any combination of the aforementioned.

[0147]

Drug-coating of, or drug incorporation into prosthetic heart valves will allow bacteriocidal drug levels to be achieved locally on the valvular surface, thus reducing the incidence of bacterial colonization and subsequent development of PVE, while producing negligible systemic exposure to the drugs. Although for some agents polymeric carriers are not required for attachment of the drug to the valve annular ring and/or leaflets, several polymeric carriers are particularly suitable for use in this embodiment. Of particular interest are polymeric carriers such as polyurethanes (e.g., ChronoFlex AL 85A [CT Biomaterials], HydroMed640™ [CT Biomaterials], HYDROSLIP C™ [CT Biomaterials], HYDROTHANE™ [CT Biomaterials]), acrylic or methacrylic copolymers (e.g. poly(ethylene-co-acrylic acid), cellulose-derived polymers (e.g., nitrocellulose, Cellulose Acetate Butyrate, Cellulose acetate propionate), acrylate and methacrylate copolymers (e.g., poly(ethylene-co-vinyl acetate)), as well as blends thereof.

[0148]

As prosthetic heart valves are made in a variety of configurations and sizes, the exact dose administered will vary with device size, surface area and design. However, certain principles can be applied in the application of this art. Drug dose can be calculated as a function of dose per unit area (of the portion of the device being coated), total drug dose administered can be measured and appropriate surface concentrations of active drug can be determined. Regardless of the method of application of the drug to the prosthetic heart valve, the preferred anticancer agents, used alone or in combination, should be administered under the following dosing guidelines:

[0149]

(a) Anthracyclines. Utilizing the anthracycline doxorubicin as an example, whether applied as a polymer coating, incorporated into the polymers which make up the prosthetic heart valve, or applied without a carrier polymer, the total dose of doxorubicin applied to the prosthetic heart valve should not exceed 25 mg (range of 0.1 μg to 25 mg). In a particularly preferred embodiment, the total amount of drug applied to the prosthetic heart valve should be in the range of 1 μg to 5 mg. The dose per unit area of the valve (i.e., the amount of drug as a function of the surface area of the portion of the valve to which drug is applied and/or incorporated) should fall within the range of 0.01 μg-100 μg per mm2 of surface area. In a particularly preferred embodiment, doxorubicin should be applied to the valve surface at a dose of 0.1 μg/mm2-10 μg/mm2. As different polymer and non-polymer coatings will release doxorubicin at differing rates, the above dosing parameters should be utilized in combination with the release rate of the drug from the valve surface such that a minimum concentration of 10−7-10−4 M of doxorubicin is maintained on the surface. It is necessary to insure that drug concentrations on the valve surface exceed concentrations of doxorubicin known to be lethal to multiple species of bacteria and fungi (i.e., are in excess of 10−4M; although for some embodiments lower concentrations are sufficient). In a preferred embodiment, doxorubicin is released from the surface of the valve such that anti-infective activity is maintained for a period ranging from several hours to several months. In a particularly preferred embodiment the drug is released in effective concentrations for a period ranging from 1-6 months. It should be readily evident based upon the discussions provided herein that analogues and derivatives of doxorubicin (as described previously) with similar functional activity can be utilized for the purposes of this invention; the above dosing parameters are then adjusted according to the relative potency of the analogue or derivative as compared to the parent compound (e.g. a compound twice as potent as doxorubicin is administered at half the above parameters, a compound half as potent as doxorubicin is administered at twice the above parameters, etc.).

[0150]

Utilizing mitoxantrone as another example of an anthracycline, whether applied as a polymer coating, incorporated into the polymers which make up the prosthetic heart valve, or applied without a carrier polymer, the total dose of mitoxantrone applied to the prosthetic heart valve should not exceed 5 mg (range of 0.01 μg to 5 mg). In a particularly preferred embodiment, the total amount of drug applied to the prosthetic heart valve should be in the range of 0.1 μg to 1 mg. The dose per unit area of the valve (i.e. the amount of drug as a function of the surface area of the portion of the valve to which drug is applied and/or incorporated) should fall within the range of 0.01 μg-20 μg per mm2 of surface area. In a particularly preferred embodiment, mitoxantrone should be applied to the valve surface at a dose of 0.05 μg/mm2-3 μg/mm2. As different polymer and non-polymer coatings will release mitoxantrone at differing rates, the above dosing parameters should be utilized in combination with the release rate of the drug from the valve surface such that a minimum concentration of 10−5-10−6 M of mitoxantrone is maintained on the valve surface. It is necessary to insure that drug concentrations on the valve surface exceed concentrations of mitoxantrone known to be lethal to multiple species of bacteria and fungi (i.e. are in excess of 10−5 M; although for some embodiments lower drug levels will be sufficient). In a preferred embodiment, mitoxantrone is released from the surface of the valve such that anti-infective activity is maintained for a period ranging from several hours to several months. In a particularly preferred embodiment the drug is released in effective concentrations for a period ranging from 1-6 months. It should be readily evident based upon the discussions provided herein that analogues and derivatives of mitoxantrone (as described previously) with similar functional activity can be utilized for the purposes of this invention; the above dosing parameters are then adjusted according to the relative potency of the analogue or derivative as compared to the parent compound (e.g. a compound twice as potent as mitoxantrone is administered at half the above parameters, a compound half as potent as mitoxantrone is administered at twice the above parameters, etc.).

[0151]

(b) Fluoropyrimidines Utilizing the fluoropyrimidine 5-fluorouracil as an example, whether applied as a polymer coating, incorporated into the polymers which make up the prosthetic heart valve, or applied without a carrier polymer, the total dose of 5-fluorouracil applied to the prosthetic heart valve should not exceed 250 mg (range of 1.0 μg to 250 mg). In a particularly preferred embodiment, the total amount of drug applied to the prosthetic heart valve should be in the range of 10 μg to 25 mg. The dose per unit area of the valve (i.e. the amount of drug as a function of the surface area of the portion of the valve to which drug is applied and/or incorporated) should fall within the range of 0.1 μg-1 mg per mm2 of surface area. In a particularly preferred embodiment, 5-fluorouracil should be applied to the valve surface at a dose of 1.0 μg/mm2-50 μg/mm2. As different polymer and non-polymer coatings will release 5-fluorouracil at differing rates, the above dosing parameters should be utilized in combination with the release rate of the drug from the valve surface such that a minimum concentration of 10−4-10−7 M of 5-fluorouracil is maintained on the valve surface. It is necessary to insure that drug concentrations on the prosthetic heart valve surface exceed concentrations of 5-fluorouracil known to be lethal to numerous species of bacteria and fungi (i.e., are in excess of 10−4 M; although for some embodiments lower drug levels will be sufficient). In a preferred embodiment, 5-fluorouracil is released from the surface of the valve such that anti-infective activity is maintained for a period ranging from several hours to several months. In a particularly preferred embodiment the drug is released in effective concentrations for a period ranging from 1-6 months. It should be readily evident based upon the discussions provided herein that analogues and derivatives of 5-fluorouracil (as described previously) with similar functional activity can be utilized for the purposes of this invention; the above dosing parameters are then adjusted according to the relative potency of the analogue or derivative as compared to the parent compound (e.g., a compound twice as potent as 5-fluorouracil is administered at half the above parameters, a compound half as potent as 5-fluorouracil is administered at twice the above parameters, etc.).

[0152]

(c) Podophylotoxins Utilizing the podophylotoxin etoposide as an example, whether applied as a polymer coating, incorporated into the polymers which make up the prosthetic heart valve, or applied without a carrier polymer, the total dose of etoposide applied to the prosthetic heart valve should not exceed 25 mg (range of 0.1 μg to 25 mg). In a particularly preferred embodiment, the total amount of drug applied to the prosthetic heart valve should be in the range of 1 μg to 5 mg. The dose per unit area of the valve (i.e., the amount of drug as a function of the surface area of the portion of the valve to which drug is applied and/or incorporated) should fall within the range of 0.01 μg-100 μg per mm2 of surface area. In a particularly preferred embodiment, etoposide should be applied to the prosthetic heart valve surface at a dose of 0.1 μg/mm2-10 μg/mm2. As different polymer and non-polymer coatings will release etoposide at differing rates, the above dosing parameters should be utilized in combination with the release rate of the drug from the valve surface such that a concentration of 10−5-10−6 M of etoposide is maintained on the valve surface. It is necessary to insure that drug concentrations on the valve surface exceed concentrations of etoposide known to be lethal to a variety of bacteria and fungi (i.e., are in excess of 10−5 M; although for some embodiments lower drug levels will be sufficient). In a preferred embodiment, etoposide is released from the surface of the valve such that anti-infective activity is maintained for a period ranging from several hours to several months. In a particularly preferred embodiment the drug is released in effective concentrations for a period ranging from 1-6 months. It should be readily evident based upon the discussions provided herein that analogues and derivatives of etoposide (as described previously) with similar functional activity can be utilized for the purposes of this invention; the above dosing parameters are then adjusted according to the relative potency of the analogue or derivative as compared to the parent compound (e.g. a compound twice as potent as etoposide is administered at half the above parameters, a compound half as potent as etoposide is administered at twice the above parameters, etc.).

The most common type of pacemaker infection involves the subcutaneous generator unit or lead wires in the period shortly after placement. This type of infection is thought to be the result of contamination of the surgical site by skin flora at the time of placement. Staphylococcus epidermidis (65-75% of cases), Stapylococcus aureus, Streptococci, Corynebacterium, Proprionibacterium acnes, Enterobacteriaceae and Candida species are frequent causes of this type of infection. Treatment of the infection at this point is relatively straightforward, the infected portion of the device is removed, the patient is treated with antibiotics and a new pacemaker is inserted at a different site. Unfortunately, infections of the generator pocket can subsequently spread to the epicardial electrodes causing more severe complications such pericarditis, mediastinitis and bacteremia.

[0156]

Infection of the intravascular portion of the tranvenous electrode poses a more significant clinical problem. This infection is thought to be caused by infection of the subcutaneous portion of the pacing apparatus that tracks along the device into the intravascular and intracardiac portions of the device. This infection tends to present at a later time (1-6 months post-procedure) and can result in sepsis, endocarditis, pneumonia, bronchitis, pulmonary embolism, cardiac vegetations and even death. Coagulase Negative Staphylococci (56% of infections), Staphylococcus aureus (27%), Enterobacteriaceae (6%), Pseudomonas arugenosa (3%) and Candida albicans (2%) are the most common cause of this serious form of pacemaker infection. Treatment of this form of infection is more complex. The generator and electrodes must be removed (often surgically), antibiotics are required for prolonged periods and an entire new pacemaker system must be inserted. Mortality rates associated with this condition can be quite high—41% if treated with antibiotics alone, 20% if treated with electrode removal and antibiotics.

[0157]

An effective cardiac pacemaker coating would reduce the incidence of subcutaneous infection and subsequent tracking of infection to the pericardial and endocardial surfaces of the heart. Clinically, this would result in a reduction in the overall rate of infection and reduce the incidence of more severe complications such as sepsis, endocarditis, pneumonia, bronchitis, pulmonary embolism, cardiac vegetations and even death. An effective coating could also prolong the effectiveness of the pacemaker and decrease the number of pacemakers requiring replacement, resulting in lower mortality and morbidity for patients with these implants.

[0158]

In a preferred embodiment, an anthracycline (e.g., doxorubicin and mitoxantrone), fluoropyrimidine (e.g., 5-FU), folic acid antagonist (e.g., methotrexate), and/or podophylotoxin (e.g., etoposide) is formulated into a coating applied to the surface of the components of the cardiac pacemaker. The drug(s) can be applied to the pacemaker in several manners: (a) as a coating applied to the surface of the generator unit; (b) as a coating applied to the surface of the subcutaneous portion of the lead wires; (c) incorporated into, or applied to the surface of, a subcutaneous “cuff” around the subcutaneous insertion site; (d) as a coating applied to the surface of the epicardial electrodes; (e) as a coating applied to the surface of the transvenous electrode; and/or (f) any combination of the aforementioned.

[0159]

Drug-coating of, or drug incorporation into cardiac pacemakers will allow bacteriocidal drug levels to be achieved locally on the pacemaker surface, thus reducing the incidence of bacterial colonization and subsequent development of infectious complications, while producing negligible systemic exposure to the drugs. Although for some agents polymeric carriers are not required for attachment of the drug to the generator unit, leads and electrodes, several polymeric carriers are particularly suitable for use in this embodiment. Of particular interest are polymeric carriers such as polyurethanes (e.g., ChronoFlex AL 85A [CT Biomaterials], HydroMed640™ [CT Biomaterials], HYDROSLIP C™ [CT Biomaterials], HYDROTHANE™ [CT Biomaterials]), acrylic or methacrylic copolymers (e.g. poly(ethylene-co-acrylic acid), cellulose-derived polymers (e.g. nitrocellulose. Cellulose Acetate Butyrate, Cellulose acetate propionate), acrylate and methacrylate copolymers (e.g. poly(ethylene-co-vinyl acetate)) as well as blends thereof.

[0160]

As cardiac pacemakers are made in a variety of configurations and sizes, the exact dose administered will vary with device size, surface area, design and portions of the pacemaker coated. However, certain principles can be applied in the application of this art. Drug dose can be calculated as a function of dose per unit area (of the portion of the device being coated), total drug dose administered can be measured and appropriate surface concentrations of active drug can be determined. Regardless of the method of application of the drug to the cardiac pacemaker, the preferred anticancer agents, used alone or in combination, should be administered under the following dosing guidelines:

[0161]

(a) Anthracyclines. Utilizing the anthracycline doxorubicin as an example, whether applied as a polymer coating, incorporated into the polymers which make up the pacemaker components, or applied without a carrier polymer, the total dose of doxorubicin applied to the pacemaker should not exceed 25 mg (range of 0.1 μg to 25 mg). In a particularly preferred embodiment, the total amount of drug applied should be in the range of 1 μg to 5 mg. The dose per unit area (i.e. the amount of drug as a function of the surface area of the portion of the pacemaker to which drug is applied and/or incorporated) should fall within the range of 0.01 μg-100 μg per mm2of surface area. In a particularly preferred embodiment, doxorubicin should be applied to the pacemaker surface at a dose of 0.1 μg/mm2-10 μg/mm2. As different polymer and non-polymer coatings will release doxorubicin at differing rates, the above dosing parameters should be utilized in combination with the release rate of the drug from the pacemaker surface such that a minimum concentration of 10−7-10−4 M of doxorubicin is maintained on the surface. It is necessary to insure that surface drug concentrations exceed concentrations of doxorubicin known to be lethal to multiple species of bacteria and fungi (i.e., are in excess of 10−4 M; although for some embodiments lower concentrations are sufficient). In a preferred embodiment, doxorubicin is released from the surface of the pacemaker such that anti-infective activity is maintained for a period ranging from several hours to several months. In a particularly preferred embodiment the drug is released in effective concentrations for a period ranging from 1 week-6 months. It should be readily evident based upon the discussions provided herein that analogues and derivatives of doxorubicin (as described previously) with similar functional activity can be utilized for the purposes of this invention; the above dosing parameters are then adjusted according to the relative potency of the analogue or derivative as compared to the parent compound (e.g. a compound twice as potent as doxorubicin is administered at half the above parameters, a compound half as potent as doxorubicin is administered at twice the above parameters, etc.).

[0162]

Utilizing mitoxantrone as another example of an anthracycline, whether applied as a polymer coating, incorporated into the polymers which make up the pacemaker, or applied without a carrier polymer, the total dose of mitoxantrone applied should not exceed 5 mg (range of 0.01 μg to 5 mg). In a particularly preferred embodiment, the total amount of drug applied should be in the range of 0.1 μg to 1 mg. The dose per unit area (i.e. the amount of drug as a function of the surface area of the portion of the pacemaker to which drug is applied and/or incorporated) should fall within the range of 0.01 μg-20 μg per mm2 of surface area. In a particularly preferred embodiment, mitoxantrone should be applied to the pacemaker surface at a dose of 0.05 μg/mm2-3 μg/mm2. As different polymer and non-polymer coatings will release mitoxantrone at differing rates, the above dosing parameters should be utilized in combination with the release rate of the drug from the pacemaker surface such that a minimum concentration of 10−5-10−6 M of mitoxantrone is maintained. It is necessary to insure that drug concentrations on the pacemaker surface exceed concentrations of mitoxantrone known to be lethal to multiple species of bacteria and fungi (i.e. are in excess of 10−5 M; although for some embodiments lower drug levels will be sufficient). In a preferred embodiment, mitoxantrone is released from the surface of the pacemaker such that anti-infective activity is maintained for a period ranging from several hours to several months. In a particularly preferred embodiment the drug is released in effective concentrations for a period ranging from 1 week-6 months. It should be readily evident based upon the discussions provided herein that analogues and derivatives of mitoxantrone (as described previously) with similar functional activity can be utilized for the purposes of this invention; the above dosing parameters are then adjusted according to the relative potency of the analogue or derivative as compared to the parent compound (e.g. a compound twice as potent as mitoxantrone is administered at half the above parameters, a compound half as potent as mitoxantrone is administered at twice the above parameters, etc.).

[0163]

(b) Fluoropyrimidines Utilizing the fluoropyrimidine 5-fluorouracil as an example, whether applied as a polymer coating, incorporated into the polymers which make up the pacemaker, or applied without a carrier polymer, the total dose of 5-fluorouracil applied should not exceed 250 mg (range of 1.0 μg to 250 mg). In a particularly preferred embodiment, the total amount of drug applied should be in the range of 10 μg to 25 mg. The dose per unit area (i.e. the amount of drug as a function of the surface area of the portion of the pacemaker to which drug is applied and/or incorporated) should fall within the range of 0.1 μg-1 mg per mm2 of surface area. In a particularly preferred embodiment, 5-fluorouracil should be applied to the pacemaker surface at a dose of 1.0 μg/mm2-50 μg/mm2. As different polymer and non-polymer coatings will release 5-fluorouracil at differing rates, the above dosing parameters should be utilized in combination with the release rate of the drug from the pacemaker surface such that a minimum concentration of 104-10−7 M of 5-fluorouracil is maintained. It is necessary to insure that surface drug concentrations exceed concentrations of 5-fluorouracil known to be lethal to numerous species of bacteria and fungi (i.e., are in excess of 10−4 M; although for some embodiments lower drug levels will be sufficient). In a preferred embodiment, 5-fluorouracil is released from the pacemaker surface such that anti-infective activity is maintained for a period ranging from several hours to several months. In a particularly preferred embodiment the drug is released in effective concentrations for a period ranging from 1 week-6 months. It should be readily evident based upon the discussions provided herein that analogues and derivatives of 5-fluorouracil (as described previously) with similar functional activity can be utilized for the purposes of this invention; the above dosing parameters are then adjusted according to the relative potency of the analogue or derivative as compared to the parent compound (e.g. a compound twice as potent as 5-fluorouracil is administered at half the above parameters, a compound half as potent as 5-fluorouracil is administered at twice the above parameters, etc.).

[0164]

(c) Podophylotoxins Utilizing the podophylotoxin etoposide as an example, whether applied as a polymer coating, incorporated into the polymers which make up the cardiac pacemaker, or applied without a carrier polymer, the total dose of etoposide applied should not exceed 25 mg (range of 0.1 μg to 25 mg). In a particularly preferred embodiment, the total amount of drug applied should be in the range of 1 μg to 5 mg. The dose per unit area (i.e. the amount of drug as a function of the surface area of the portion of the pacemaker to which drug is applied and/or incorporated) should fall within the range of 0.01 μg-100 μg per mm2 of surface area. In a particularly preferred embodiment, etoposide should be applied to the pacemaker surface at a dose of 0.1 μg/mm2-10 μg/mm2. As different polymer and non-polymer coatings will release etoposide at differing rates, the above dosing parameters should be utilized in combination with the release rate of the drug from the pacemaker surface such that a concentration of 10−5-10−6 M of etoposide is maintained. It is necessary to insure that surface drug concentrations exceed concentrations of etoposide known to be lethal to a variety of bacteria and fungi (i.e. are in excess of 10−5 M; although for some embodiments lower drug levels will be sufficient). In a preferred embodiment, etoposide is released from the surface of the pacemaker such that anti-infective activity is maintained for a period ranging from several hours to several months. In a particularly preferred embodiment the drug is released in effective concentrations for a period ranging from 1 week-6 months. It should be readily evident based upon the discussions provided herein that analogues and derivatives of etoposide (as described previously) with similar functional activity can be utilized for the purposes of this invention; the above dosing parameters are then adjusted according to the relative potency of the analogue or derivative as compared to the parent compound (e.g. a compound twice as potent as etoposide is administered at half the above parameters, a compound half as potent as etoposide is administered at twice the above parameters, etc.).

Overall, approximately 5-10% of implantable cardioverter-defibrillators become infected following implantation (the rate is highest if surgical placement is required). Like cardiac pacemakers, implantable defibrillators are subject to infection in two general manners: (a) infections involving the subcutaneous portion of the device (subcutaneous electrodes and pulse generator unit, and (b) infections involving the intrathoracic components (rate sensing electrode, SVC coil electrode and epicardial electrodes). Representative examples of ICD's and associated components are described in U.S. Pat. Nos. 3,614,954, 3,614,955, 4,375,817, 5,314,430, 5,405,363, 5,607,385, 5,697,953, 5,776,165, 6,067,471, 6,169,923, and 6,152,955.

[0167]

Most infections present period shortly after placement and are thought to be the result of contamination of the surgical site by skin flora. Staphylococcus epidermidis, Stapylococcus aureus, Streptococci, Corynebacterium, Proprionibacterium acnes, Enterobacteriaceae and Candida species are frequent causes of this type of infection. Unfortunately, treatment frequently involves removal of the entire system and prolonged antibiotic therapy.

[0168]

An effective ICD coating would reduce the incidence of infection-related side effects such subcutaneous infection, sepsis and pericarditis. An effective coating could also prolong the effectiveness of the ICD and decrease the number of patients requiring replacement, resulting in lower mortality and morbidity associated with these implants.

[0169]

In a preferred embodiment, doxorubicin, mitoxantrone, 5-fluorouracil and/or etoposide are formulated into a coating applied to the surface of the components of the ICD. The drug(s) can be applied in several manners: (a) as a coating applied to the surface of the pulse generator unit; (b) as a coating applied to the surface of the subcutaneous portion of the lead wires; (c) incorporated into, or applied to the surface of, a subcutaneous “cuff” around the subcutaneous insertion site; (d) as a coating applied to the surface of the SVC coil electrode; (e) as a coating applied to the surface of the epicardial electrode; and/or (f) any combination of the aforementioned.

[0170]

Drug-coating of, or drug incorporation into prosthetic heart valves will allow bacteriocidal drug levels to be achieved locally on the ICD surface, thus reducing the incidence of bacterial colonization and subsequent development of infectious complications, while producing negligible systemic exposure to the drugs. Although for some agents polymeric carriers are not required for attachment of the drug to the generator unit, leads and electrodes, several polymeric carriers are particularly suitable for use in this embodiment. Of particular interest are polymeric carriers such as polyurethanes (e.g., ChronoFlex AL 85A [CT Biomaterials], HydroMed640™ [CT Biomaterials], HYDROSLIP C™ [CT Biomaterials], HYDROTHANE™ [CT Biomaterials]), acrylic or methacrylic copolymers (e.g. poly(ethylene-co-acrylic acid), cellulose-derived polymers (e.g. nitrocellulose, Cellulose Acetate Butyrate, Cellulose acetate propionate), acrylate and methacrylate copolymers (e.g. poly(ethylene-co-vinyl acetate)) as well as blends thereof.

[0171]

As implantable cardioverter-defibrillators have many design features similar to those found in cardiac pacemakers, the dosing guidelines for doxorubicin, mitoxantrone, 5-fluorouracil and etoposide in coating ICDs are identical to those described above for cardiac pacemakers.

E. Vascular Graft Infections

[0172]

Infection rates for synthetic vascular grafts range from 1-5% and are highest in grafts that traverse the inguinal region (such as aorto-femoral grafts and femoral-popliteal grafts). Although infection can result from extension of an infection from an adjacent contaminated tissue or hematogenous seeding, the most common cause of infection is intraoperative contamination. In fact, more than half of all cases present within the first 3 months after surgery.. The most common causes of infection include Staphylococcus aureus (25-35% of cases), Enterobacteriaceae, Pseudomonas aerugenosa, and Coagulase Negative Staphylococci.

[0173]

Complications arising from vascular graft infection include sepsis, subcutaneous infection, false aneurysm formation, graft thrombosis, haemorrhage, septic or thrombotic emboli and graft thrombosis. Treatment requires removal of the graft in virtually all cases combined with systemic antibiotics. Often the surgery must be performed in a staged manner (complete resection of the infected graft, debridement of adjacent infected tissues, development of a healthy arterial stump, reperfusion through an uninfected pathway) further adding to the morbidity and mortality associated with this condition. For example, if an aortic graft becomes infected there is a 37% mortality rate and a 21% rate of leg amputation in survivors; for infrainguinal grafts the rates are 18% and 40% respectively.

An effective vascular graft coating would reduce the incidence of complications such as sepsis, haemorrhage, thrombosis, embolism, amputation and even death. An effective coating would also decrease the number of vascular grafts requiring replacement, resulting in lower mortality and morbidity for patients with these implants.

[0176]

In a preferred embodiment, an anthracycline (e.g., doxorubicin and mitoxantrone), fluoropyrimidine (e.g., 5-FU), folic acid antagonist (e.g., methotrexate), and/or podophylotoxin (e.g., etoposide) is formulated into a coating applied to the surface of the components of the vascular graft. The drug(s) can be applied in several manners: (a) as a coating applied to the external surface of the graft; (b) as a coating applied to the internal (luminal) surface of the graft; and/or (c) as a coating applied to all or parts of both surfaces.

[0177]

Drug-coating of, or drug incorporation into vascular grafts will allow bacteriocidal drug levels to be achieved locally on the graft surface, thus reducing the incidence of bacterial colonization and subsequent development of infectious complications, while producing negligible systemic exposure to the drugs. Although for some agents polymeric carriers are not required for attachment of the drug, several polymeric carriers are particularly suitable for use in this embodiment. Of particular interest are polymeric carriers such as polyurethanes (e.g., ChronoFlex AL 85A [CT Biomaterials], HydroMed640™ (CT Biomaterials], HYDROSLIP C™ [CT Biomaterials], HYDROTHANE™ [CT Biomateriais]), acrylic or methacrylic copolymers (e.g. poly(ethylene-co-acrylic acid), cellulose-derived polymers (e.g. nitrocellulose, Cellulose Acetate Butyrate, Cellulose acetate propionate), acrylate and methacrylate copolymers (e.g. poly(ethylene-co-vinyl acetate)) collagen as well as blends thereof.

[0178]

As vascular grafts are made in a variety of configurations and sizes, the exact dose administered will vary with device size, surface area, design and portions of the graft coated. However, certain principles can be applied in the application of this art. Drug dose can be calculated as a function of dose per unit area (of the portion of the device being coated), total drug dose administered can be measured and appropriate surface concentrations of active drug can be determined. Regardless of the method of application of the drug to the vascular graft, the preferred anticancer agents, used alone or in combination, should be administered under the following dosing guidelines:

[0179]

(a) Anthracyclines. Utilizing the anthracycline doxorubicin as an example, whether applied as a polymer coating, incorporated into the polymers which make up the vascular graft components (such as Dacron or Teflon), or applied without a carrier polymer, the total dose of doxorubicin applied should not exceed 25 mg (range of 0.1 μg to 25 mg). In a particularly preferred embodiment, the total amount of drug applied should be in the range of 1 μg to 5 mg. The dose per unit area (i.e. the amount of drug as a function of the surface area of the portion of the vascular graft to which drug is applied and/or incorporated) should fall within the range of 0.01 μg-100 μg per mm2 of surface area. In a particularly preferred embodiment, doxorubicin should be applied to the vascular graft surface at a dose of 0.1 μg/mm2-10 μg/mm2. As different polymer and non-polymer coatings will release doxorubicin at differing rates, the above dosing parameters should be utilized in combination with the release rate of the drug from the vascular graft surface such that a minimum concentration of 10−7-10−4 M of doxorubicin is maintained on the surface. It is necessary to insure that surface drug concentrations exceed concentrations of doxorubicin known to be lethal to multiple species of bacteria and fungi (i.e., are in excess of 10−4M; although for some embodiments lower concentrations are sufficient). In a preferred embodiment, doxorubicin is released from the surface of the vascular graft such that anti-infective activity is maintained for a period ranging from several hours to several months. In a particularly preferred embodiment the drug is released in effective concentrations for a period ranging from 1 week-6 months. It should be readily evident based upon the discussions provided herein that analogues and derivatives of doxorubicin (as described previously) with similar functional activity can be utilized for the purposes of this invention; the above dosing parameters are then adjusted according to the relative potency of the analogue or derivative as compared to the parent compound (e.g. a compound twice as potent as doxorubicin is administered at half the above parameters, a compound half as potent as doxorubicin is administered at twice the above parameters, etc.).

[0180]

Utilizing mitoxantrone as another example of an anthracycline, whether applied as a polymer coating, incorporated into the polymers which make up the vascular graft (such as Dacron or Teflon), or applied without a carrier polymer, the total dose of mitoxantrone applied should not exceed 5 mg (range of 0.01 μg to 5 mg). In a particularly preferred embodiment, the total amount of drug applied should be in the range of 0.1 μg to 1 mg. The dose per unit area (i.e. the amount of drug as a function of the surface area of the portion of the vascular graft to which drug is applied and/or incorporated) should fall within the range of 0.01 μg-20 μg per mm2 of surface area. In a particularly preferred embodiment, mitoxantrone should be applied to the vascular graft surface at a dose of 0.05 μg/mm2-3 μg/mm2. As different polymer and non-polymer coatings will release mitoxantrone at differing rates, the above dosing parameters should be utilized in combination with the release rate of the drug from the vascular graft surface such that a minimum concentration of 10−5-10−6 M of mitoxantrone is maintained. It is necessary to insure that drug concentrations on the surface exceed concentrations of mitoxantrone known to be lethal to multiple species of bacteria and fungi (i.e. are in excess of 10−5 M; although for some embodiments lower drug levels will be sufficient). In a preferred embodiment, mitoxantrone is released from the vascular graft surface such that anti-infective activity is maintained for a period ranging from several hours to several months. In a particularly preferred embodiment the drug is released in effective concentrations for a period ranging from 1 week-6 months. It should be readily evident based upon the discussions provided herein that analogues and derivatives of mitoxantrone (as described previously) with similar functional activity can be utilized for the purposes of this invention; the above dosing parameters are then adjusted according to the relative potency of the analogue or derivative as compared to the parent compound (e.g. a compound twice as potent as mitoxantrone is administered at half the above parameters, a compound half as potent as mitoxantrone is administered at twice the above parameters, etc.).

[0181]

(b) Fluoropyrimidines Utilizing the fluoropyrimidine 5-fluorouracil as an example, whether applied as a polymer coating, incorporated into the polymers which make up the vascular graft (such as Dacron or Teflon), or applied without a carrier polymer, the total dose of 5-fluorouracil applied should not exceed 250 mg (range of 1.0 μg to 250 mg). In a particularly preferred embodiment, the total amount of drug applied should be in the range of 10 μg to 25 mg. The dose per unit area (i.e. the amount of drug as a function of the surface area of the portion of the vascular graft to which drug is applied and/or incorporated) should fall within the range of 0.1 μg-1 mg per mm2 of surface area. In a particularly preferred embodiment, 5-fluorouracil should be applied to the vascular graft surface at a dose of 1.0 μg/mm2-50 μg/mm2. As different polymer and non-polymer coatings will release 5-fluorouracil at differing rates, the above dosing parameters should be utilized in combination with the release rate of the drug from the vascular graft surface such that a minimum concentration of 10−4-10−7 M of 5-fluorouracil is maintained. It is necessary to insure that surface drug concentrations exceed concentrations of 5-fluorouracil known to be lethal to numerous species of bacteria and fungi (i.e., are in excess of 10−4M; although for some embodiments lower drug levels will be sufficient). In a preferred embodiment, 5-fluorouracil is released from the vascular graft surface such that anti-infective activity is maintained for a period ranging from several hours to several months. In a particularly preferred embodiment the drug is released in effective concentrations for a period ranging from 1 week-6 months. It should be readily evident based upon the discussions provided herein that analogues and derivatives of 5-fluorouracil (as described previously) with similar functional activity can be utilized for the purposes of this invention; the above dosing parameters are then adjusted according to the relative potency of the analogue or derivative as compared to the parent compound (e.g. a compound twice as potent as 5-fluorouracil is administered at half the above parameters, a compound half as potent as 5-fluorouracil is administered at twice the above parameters, etc.).

[0182]

(c) Podophylotoxins Utilizing the podophylotoxin etoposide as an example, whether applied as a polymer coating, incorporated into the polymers which make up the vascular graft (such as Dacron or Teflon), or applied without a carrier polymer, the total dose of etoposide applied should not exceed 25 mg (range of 0.1 μg to 25 mg). In a particularly preferred embodiment, the total amount of drug applied should be in the range of 1 μg to 5 mg. The dose per unit area (i.e. the amount of drug as a function of the surface area of the portion of the vascular graft to which drug is applied and/or incorporated) should fall within the range of 0.01 μg-100 μg per mm2 of surface area. In a particularly preferred embodiment, etoposide should be applied to the vascular graft surface at a dose of 0.1 μg/mm2-10 μg/mm2. As different polymer and non-polymer coatings will release etoposide at differing rates, the above dosing parameters should be utilized in combination with the release rate of the drug from the vascular graft surface such that a concentration of 10−5-10−6 M of etoposide is maintained. It is necessary to insure that surface drug concentrations exceed concentrations of etoposide known to be lethal to a variety of bacteria and fungi (i.e. are in excess of 10−5 M; although for some embodiments lower drug levels will be sufficient). In a preferred embodiment, etoposide is released from the surface of the vascular graft such that anti-infective activity is maintained for a period ranging from several hours to several months. In a particularly preferred embodiment the drug is released in effective concentrations for a period ranging from 1 week-6 months. It should be readily evident based upon the discussions provided herein that analogues and derivatives of etoposide (as described previously) with similar functional activity can be utilized for the purposes of this invention; the above dosing parameters are then adjusted according to the relative potency of the analogue or derivative as compared to the parent compound (e.g. a compound twice as potent as etoposide is administered at half the above parameters, a compound half as potent as etoposide is administered at twice the above parameters, etc.).

Bacterial infections involving the ear, nose and throat are common occurrences in both children and adults. For the management of chronic obstruction secondary to persistent infection, the use of implanted medical tubes is a frequent form of treatment. Specifically, chronic otitis media is often treated with the surgical implantation of tympanostomy tubes and chronic sinusitis is frequently treated with surgical drainage and the placement of a sinus stent.

[0185]

Tympanostomy Tubes

[0186]

Acute otitis media is the most common bacterial infection, the most frequent indication for surgical therapy, the leading cause of hearing loss and a common cause of impaired language development in children. The cost of treating this condition in children under the age of five is estimated at $5 billion annually in the United States alone. In fact, 85% of all children will have at least one episode of otitis media and 600,000 will require surgical therapy annually. The prevalence of otitis media is increasing and for severe cases surgical therapy is more cost effective than conservative management.

[0187]

Acute otitis media (bacterial infection of the middle ear) is characterized by Eustachian tube dysfunction leading to failure of the middle ear clearance mechanism. The most common causes of otitis media are Streptococcus pneumoniae (30%), Haemophilus influenza (20%), Branhamella catarrhalis (12%), Streptococcus pyogenes (3%), and Staphylococcus aureus (1.5%). The end result is the accumulation of bacteria, white blood cells and fluid which, in the absence of an ability to drain through the Eustachian tube, results in increased pressure in the middle ear. For many cases antibiotic therapy is sufficient treatment and the condition resolves. However, for a significant number of patients the condition becomes frequently recurrent or does not resolve completely. In recurrent otitis media or chronic otitis media with effusion, there is a continuous build-up of fluid and bacteria that creates a pressure gradient across the tympanic membrane causing pain and impaired hearing. Fenestration of the tympanic membrane (typically with placement of a tympanostomy tube) relieves the pressure gradient and facilitates drainage of the middle ear (through the outer ear instead of through the Eustachian tube—a form of “Eustachian tube bypass”).

[0188]

Surgical placement of tympanostomy tubes is the most widely used treatment for chronic otitis media because, although not curative, it improves hearing (which in turn improves language development) and reduces the incidence of acute otitis media. Tympanostomy tube placement is one of the most common surgical procedures in the United States with 1.3 million surgical placements per year. Nearly all younger children and a large percentage of older children require general anaesthesia for placement. Since general anaesthesia has a higher incidence of significant side effects in children (and represents the single greatest risk and cost associated with the procedure), it is desirable to limit the number of anaesthetics that the child is exposed to. Common complications of tympanostomy tube insertion include chronic otorrhea (often due to infection by S. pneumoniae, H. influenza, Pseudomonas aerugenosa, S.aureus, or Candida), foreign body reaction with the formation of granulation tissue and infection, plugging (usually obstructed by granulation tissue, bacteria and/or clot), tympanic membrane perforation, myringosclerosis, tympanic membrane atrophy (retraction, atelectasis), and cholesteatoma.

[0189]

An effective tympanostomy tube coating would allow easy insertion, remain in place for as long as is required, be easily removed in the office without anaesthesia, resist infection and prevent the formation of granulation tissue in the tube (which can not only lead to obstruction, but also “tack down” the tube such that surgical removal of the tube under anaesthetic becomes necessary). An effective tympanostomy tube would also reduce the incidence of complications such as chronic otorrhea (often due to infection by S. pneumoniae, H. influenza, Pseudomonas aerugenosa, S. aureus, or Candida); maintain patency (prevent obstruction by granulation tissue, bacteria and/or clot); and/or reduce tympanic membrane perforation, myringoscierosis, tympanic membrane atrophy and cholesteatoma. Therefore, development of a tube which does not become obstructed by granulation tissue, does not scar in place and is less prone to infection (thereby reducing the need to remove/replace the tube) would be a significant medical advancement.

[0190]

In a preferred embodiment, doxorubicin, mitoxantrone, 5-fluorouracil and/or etoposide are formulated into a coating applied to the surface of the tympanostomy tube. The drug(s) can be applied in several manners: (a) as a coating applied to the external surface of the tympanostomy tube; (b) as a coating applied to the internal (luminal) surface of the tympanostomy tube; (c) as a coating applied to all or parts of both surfaces; and/or (d) incorporated into the polymers which comprise the tympanostomy tube.

[0191]

Drug-coating of, or drug incorporation into, the tympanostomy tube will allow bacteriocidal drug levels to be achieved locally on the tube surface, thus reducing the incidence of bacterial colonization (and subsequent development of middle ear infection), while producing negligible systemic exposure to the drugs. Although for some agents polymeric carriers are not required for attachment of the drug to the tympanostomy tube surface, several polymeric carriers are particularly suitable for use in this embodiment. Of particular interest are polymeric carriers such as polyurethanes (e.g., ChronoFlex AL 85A [CT Biomaterials], HydroMed640™ [CT Biomaterials], HYDROSLIP C™ [CT Biomaterials], HYDROTHANE™ [CT Biomaterials]), acrylic or methacrylic copolymers (e.g. poly(ethylene-co-acrylic acid), cellulose-derived polymers (e.g. nitrocellulose, Cellulose Acetate Butyrate, Cellulose acetate propionate), acrylate and methacrylate copolymers (e.g. poly(ethylene-co-vinyl acetate)) as well as blends thereof.

[0192]

There are two general designs of tympanostomy tubes: grommet-shaped tubes, which tend to stay in place for less than 1 year but have a low incidence of permanent perforation of the tympanic membrane (1%), and T-tubes, which stay in place for several years but have a higher rate of permanent perforation (5%). As tympanostomy tubes are made in a variety of configurations and sizes, the exact dose administered will vary with device size, surface area and design. However, certain principles can be applied in the application of this art. Drug dose can be calculated as a function of dose per unit area (of the portion of the device being coated), total drug dose administered can be measured and appropriate surface concentrations of active drug can be determined. Regardless of the method of application of the drug to the tympanostomy tube, the preferred anticancer agents, used alone or in combination, should be administered under the following dosing guidelines:

[0193]

(a) Anthracyclines. Utilizing the anthracycline doxorubicin as an example, whether applied as a polymer coating, incorporated into the polymers which make up the tympanostomy tube components, or applied without a carrier polymer, the total dose of doxorubicin applied should not exceed 25 mg (range of 0.1 μg to 25 mg). In a particularly preferred embodiment, the total amount of drug applied should be in the range of 1 μg to 5 mg. The dose per unit area (i.e. the amount of drug as a function of the surface area of the portion of the tympanostomy tube to which drug is applied and/or incorporated) should fall within the range of 0.01 μg-100 μg per mm2 of surface area. In a particularly preferred embodiment, doxorubicin should be applied to the tympanostomy tube surface at a dose of 0.1 μg/mm2-10 μg/mm2. As different polymer and non-polymer coatings will release doxorubicin at differing rates, the above dosing parameters should be utilized in combination with the release rate of the drug from the tympanostomy tube surface such that a minimum concentration of 10−7-10−4 M of doxorubicin is maintained on the surface. It is necessary to insure that surface drug concentrations exceed concentrations of doxorubicin known to be lethal to multiple species of bacteria and fungi (i.e., are in excess of 10−4 M; although for some embodiments lower concentrations are sufficient). In a preferred embodiment, doxorubicin is released from the surface of the tympanostomy tube such that anti-infective activity is maintained for a period ranging from several hours to several months. In a particularly preferred embodiment the drug is released in effective concentrations for a period ranging from 1 week-6 months. It should be readily evident based upon the discussions provided herein that analogues and derivatives of doxorubicin (as described previously) with similar functional activity can be utilized for the purposes of this invention; the above dosing parameters are then adjusted according to the relative potency of the analogue or derivative as compared to the parent compound (e.g. a compound twice as potent as doxorubicin is administered at half the above parameters, a compound half as potent as doxorubicin is administered at twice the above parameters, etc.).

[0194]

Utilizing mitoxantrone as another example of an anthracycline, whether applied as a polymer coating, incorporated into the polymers which make up the tympanostomy tube, or applied without a carrier polymer, the total dose of mitoxantrone applied should not exceed 5 mg (range of 0.01 μg to 5 mg). In a particularly preferred embodiment, the total amount of drug applied should be in the range of 0.1 μg to 1 mg. The dose per unit area (i.e. the amount of drug as a function of the surface area of the portion of the tympanostomy tube to which drug is applied and/or incorporated) should fall within the range of 0.01 μg-20 μg per mm2 of surface area. In a particularly preferred embodiment, mitoxantrone should be applied to the tympanostomy tube surface at a dose of 0.05 μg/mm2-3 μg/mm2. As different polymer and non-polymer coatings will release mitoxantrone at differing rates, the above dosing parameters should be utilized in combination with the release rate of the drug from the tympanostomy tube surface such that a minimum concentration of 10−5-10−6 M of mitoxantrone is maintained. It is necessary to insure that drug concentrations on the surface exceed concentrations of mitoxantrone known to be lethal to multiple species of bacteria and fungi (i.e. are in excess of 10−5 M; although for some embodiments lower drug levels will be sufficient). In a preferred embodiment, mitoxantrone is released from the tympanostomy tube surface such that anti-infective activity is maintained for a period ranging from several hours to several months. In a particularly preferred embodiment the drug is released in effective concentrations for a period ranging from 1 week-6 months. It should be readily evident based upon the discussions provided herein that analogues and derivatives of mitoxantrone (as described previously) with similar functional activity can be utilized for the purposes of this invention; the above dosing parameters are then adjusted according to the relative potency of the analogue or derivative as compared to the parent compound (e.g. a compound twice as potent as mitoxantrone is administered at half the above parameters, a compound half as potent as mitoxantrone is administered at twice the above parameters, etc.).

[0195]

(b) Fluoropyrimidines Utilizing the fluoropyrimidine 5-fluorouracil as an example, whether applied as a polymer coating, incorporated into the polymers which make up the tympanostomy tube, or applied without a carrier polymer, the total dose of 5-fluorouracil applied should not exceed 250 mg (range of 1.0 μg to 250 mg). In a particularly preferred embodiment, the total amount of drug applied should be in the range of 10 μg to 25 mg. The dose per unit area (i.e. the amount of drug as a function of the surface area of the portion of the tympanostomy tube to which drug is applied and/or incorporated) should fall within the range of 0.1 μg-1 mg per mm2 of surface area. In a particularly preferred embodiment, 5-fluorouracil should be applied to the tympanostomy tube surface at a dose of 1.0 μg/mm2-50 μg/mm2. As different polymer and non-polymer coatings will release 5-fluorouracil at differing rates, the above dosing parameters should be utilized in combination with the release rate of the drug from the tympanostomy tube surface such that a minimum concentration of 10−4-10−7 M of 5-fluorouracil is maintained. It is necessary to insure that surface drug concentrations exceed concentrations of 5-fluorouracil known to be lethal to numerous species of bacteria and fungi (i.e., are in excess of 10−4 M; although for some embodiments lower drug levels will be sufficient). In a preferred embodiment, 5-fluorouracil is released from the tympanostomy tube surface such that anti-infective activity is maintained for a period ranging from several hours to several months. In a particularly preferred embodiment the drug is released in effective concentrations for a period ranging from 1 week-6 months. It should be readily evident given the discussions provided herein that analogues and derivatives of 5-fluorouracil (as described previously) with similar functional activity can be utilized for the purposes of this invention; the above dosing parameters are then adjusted according to the relative potency of the analogue or derivative as compared to the parent compound (e.g. a compound twice as potent as 5-fluorouracil is administered at half the above parameters, a compound half as potent as 5-fluorouracil is administered at twice the above parameters, etc.).

[0196]

(c) Podophylotoxins Utilizing the podophylotoxin etoposide as an example, whether applied as a polymer coating, incorporated into the polymers which make up the tympanostomy tube, or applied without a carrier polymer, the total dose of etoposide applied should not exceed 25 mg (range of 0.1 μg to 25 mg). In a particularly preferred embodiment, the total amount of drug applied should be in the range of 1 μg to 5 mg. The dose per unit area (i.e. the amount of drug as a function of the surface area of the portion of the tympanostomy tube to which drug is applied and/or incorporated) should fall within the range of 0.01 μg-100 μg per mm2 of surface area. In a particularly preferred embodiment, etoposide should be applied to the tympanostomy tube surface at a dose of 0.1 μg/mm2-10 μg/mm2. As different polymer and non-polymer coatings will release etoposide at differing rates, the above dosing parameters should be utilized in combination with the release rate of the drug from the tympanostomy tube surface such that a concentration of 10−5-10−6 M of etoposide is maintained. It is necessary to insure that surface drug concentrations exceed concentrations of etoposide known to be lethal to a variety of bacteria and fungi (i.e. are in excess of 10−5 M; although for some embodiments lower drug levels will be sufficient). In a preferred embodiment, etoposide is released from the surface of the tympanostomy tube such that anti-infective activity is maintained for a period ranging from several hours to several months. In a particularly preferred embodiment the drug is released in effective concentrations for a period ranging from 1 week-6 months. It should be readily evident given the discussions provided herein that analogues and derivatives of etoposide (as described previously) with similar functional activity can be utilized for the purposes of this invention; the above dosing parameters are then adjusted according to the relative potency of the analogue or derivative as compared to the parent compound (e.g. a compound twice as potent as etoposide is administered at half the above parameters, a compound half as potent as etoposide is administered at twice the above parameters, etc.).

The sinuses are four pairs of hollow regions contained in the bones of the skull named after the bones in which they are located (ethmoid, maxillary, frontal and sphenoid). All are lined by respiratory mucosa which is directly attached to the bone. Following an inflammatory insult such as an upper respiratory tract infection or allergic rhinitis, a purulent form of sinusitis can develop. Occasionally secretions can be retained in the sinus due to altered ciliary function or obstruction of the opening (ostea) that drains the sinus. Incomplete drainage makes the sinus prone to infection typically with Haemophilus influenza, Streptococcus pneumoniae, Moraxella catarrhalis, Veillonella, Peptococcus, Corynebacterium acnes and certain species of fungi.

[0200]

When initial treatment such as antibiotics, intranasal steroid sprays and decongestants are ineffective, it may become necessary to perform surgical drainage of the infected sinus. Surgical therapy often involves debridement of the ostea to remove anatomic obstructions and removal of parts of the mucosa. Occasionally a stent (a cylindrical tube which physically holds the lumen of the ostea open) is left in the osta to ensure drainage is maintained even in the presence of postoperative swelling. Stents, typically made of stainless steel or plastic, remain in place for several days or several weeks before being removed.

[0201]

Unfortunately, the stents can become infected or overgrown by granulation tissue that renders them ineffective. An effective sinus stent coating would allow easy insertion, remain in place for as long as is required, be easily removed in the office without anaesthesia, resist infection and prevent the formation of granulation tissue in the stent (which can not only lead to obstruction, but also “tack down” the stent such that surgical removal becomes necessary). Therefore, development of a sinus stent which does not become obstructed by granulation tissue, does not scar in place and is less prone to infection would be beneficial.

[0202]

In a preferred embodiment, doxorubicin, mitoxantrone, 5-fluorouracil and/or etoposide are formulated into a coating applied to the surface of the sinus stent. The drug(s) can be applied in several manners: (a) as a coating applied to the external surface of the sinus stent; (b) as a coating applied to the internal (luminal) surface of the sinus stent; (c) as a coating applied to all or parts of both surfaces; and/or (d) incorporated into the polymers which comprise the sinus stent.

[0203]

Drug-coating of, or drug incorporation into, the sinus stent will allow bacteriocidal drug levels to be achieved locally on the tube surface, thus reducing the incidence of bacterial colonization (and subsequent development of sinusitis), while producing negligible systemic exposure to the drugs. Although for some agents polymeric carriers are not required for attachment of the drug to the sinus stent surface, several polymeric carriers are particularly suitable for use in this embodiment. Of particular interest are polymeric carriers such as polyurethanes (e.g., ChronoFlex AL 85A [CT Biomaterials], HydroMed640 ™ [CT Biomaterials], HYDROSLIP C™ [CT Biomaterials], HYDROTHANE™ [CT Biomaterials]), acrylic or methacrylic copolymers (e.g. poly(ethylene-co-acrylic acid), cellulose-derived polymers (e.g. nitrocellulose, Cellulose Acetate Butyrate, Cellulose acetate propionate), acrylate and methacrylate copolymers (e.g. poly(ethylene-co-vinyl acetate)) as well as blends thereof.

[0204]

As sinus stents are prone to the same complications and infections from the same bacteria, the dosing guidelines for doxorubicin, mitoxantrone, 5-fluorouracil and etoposide in coating sinus stents are identical to those described above for tympanostomy tubes.

G. Infections Associated with Urological Implants

[0205]

Implanted medical devices are used in the urinary tract with greater frequency than in any other body system and have some of the highest rates of infection. In fact, the great majority of urinary devices become infected if they remain in place for a prolonged period of time and are the most common cause of nosocomial infection.

[0206]

Urinary (Foley) Catheters

[0207]

Four-to-five million bladder catheters are inserted into hospitalized patients every year in the United States. The duration of catheterization is the important risk factor for patients developing a clinically significant infection—the rate of infection increases 5-10% per day that the patient is catheterized. Although simple cystitis can be treated with a short course of antibiotics (with or without removal of the catheter), serious complications are frequent and can be extremely serious. The infection can ascend to the kidneys causing acute pyelonephritis which can result in scarring and long term kidney damage. Perhaps of greatest concern is the 1-2% risk of developing gram negative sepsis (the risk is 3-times higher in catheterized patients and accounts for 30% of all cases) which can be extremely difficult to treat and can result in septic shock and death (up to 50% of patients). Therefore, there exists a significant medical need to produce improved urinary catheters capable of reducing the incidence of urinary tract infection in catheterized patients.

[0208]

The most common cause of infection is bacteria typically found in the bowel or perineum that are able to track up the catheter to gain access to the normally sterile bladder. Bacteria can be carried into the bladder as the catheter is inserted, gain entry via the sheath of exudates that surrounds the catheter, and/or travel intraluminally inside the catheter tubing. Several species of bacteria are able to adhere to the catheter and form a biofilm that provides a protected site for growth. With short-term catheterization, single organism infections are most common and are typically due to Escherichia coli, Enterococci, Pseudomonas aeruginosa, Klebsiella, Proteus, Enterobacter, Staphylococcus epidermidis, Staphylococcus aureus and Staphylococcus saprophyticus. Patients who are catheterized for long periods of time are prone to polymicrobial infections caused by all of the organisms previously mentioned as well as Providencia stuartii, Morganella morganii and Candida. Antibiotic use either systemically or locally has been largely proven to be ineffective as it tends to result only in the selection of drug-resistant bacteria.

[0209]

An effective urinary catheter coating would allow easy insertion into the bladder, resist infection and prevent the formation of biofilm in the catheter. An effective coating would prevent or reduce the incidence of urinary tract infection, pyelonephritis, and/or sepsis. In a preferred embodiment, doxorubicin, mitoxantrone, 5-fluorouracil and/or etoposide are formulated into a coating applied to the surface of the urinary catheter. The drug(s) can be applied in several manners: (a) as a coating applied to the external surface of the urinary catheter; (b) as a coating applied to the internal (luminal) surface of the urinary catheter; (c) as a coating applied to all or parts of both surfaces; and/or (d) incorporated into the polymers which comprise the urinary catheter.

[0210]

Drug-coating of, or drug incorporation into, the urinary catheter will allow bacteriocidal drug levels to be achieved locally on the catheter surface, thus reducing the incidence of bacterial colonization (and subsequent development of urinary tract infection and bacteremia), while producing negligible systemic exposure to the drugs. Although for some agents polymeric carriers are not required for attachment of the drug to the urinary catheter surface, several polymeric carriers are particularly suitable for use in this embodiment. Of particular interest are polymeric carriers such as polyurethanes (e.g., ChronoFlex AL 85A [CT Biomaterials], HydroMed640™ [CT Biomaterials], HYDROSLIP C™ [CT Biomaterials], HYDROTHANE™ [CT Biomaterials]), acrylic or methacrylic copolymers (e.g. poly(ethylene-co-acrylic acid), cellulose-derived polymers (e.g. nitrocellulose, Cellulose Acetate Butyrate, Cellulose acetate propionate), acrylate and methacrylate copolymers (e.g. poly(ethylene-co-vinyl acetate)) as well as blends thereof.

[0211]

As urinary catheters (e.g. Foley catheters, suprapubic catheters) are made in a variety of configurations and sizes, the exact dose administered will vary with device size, surface area and design. However, certain principles can be applied in the application of this art. Drug dose can be calculated as a function of dose per unit area (of the portion of the device being coated), total drug dose administered can be measured and appropriate surface concentrations of active drug can be determined. Regardless of the method of application of the drug to the urinary catheter, the preferred anticancer agents, used alone or in combination, should be administered under the following dosing guidelines:

[0212]

(a) Anthracyclines. Utilizing the anthracycline doxorubicin as an example, whether applied as a polymer coating, incorporated into the polymers which make up the urinary catheter components, or applied without a carrier polymer, the total dose of doxorubicin applied should not exceed 25 mg (range of 0.1 μg to 25 mg). In a particularly preferred embodiment, the total amount of drug applied should be in the range of 1 μg to 5 mg. The dose per unit area (i.e. the amount of drug as a function of the surface area of the portion of the urinary catheter to which drug is applied and/or incorporated) should fall within the range of 0.01 μg-100 μg per mm2 of surface area. In a particularly preferred embodiment, doxorubicin should be applied to the urinary catheter surface at a dose of 0.1 μg/mm2-10 μg/mm2. As different polymer and non-polymer coatings will release doxorubicin at differing rates, the above dosing parameters should be utilized in combination with the release rate of the drug from the urinary catheter surface such that a minimum concentration of 10−7-10−4 M of doxorubicin is maintained on the surface. It is necessary to insure that surface drug concentrations exceed concentrations of doxorubicin known to be lethal to multiple species of bacteria and fungi (i.e., are in excess of 10−4 M; although for some embodiments lower concentrations are sufficient). In a preferred embodiment, doxorubicin is released from the surface of the urinary catheter such that anti-infective activity is maintained for a period ranging from several hours to several months. In a particularly preferred embodiment the drug is released in effective concentrations for a period ranging from 1 hour-1 month. It should be readily evident given the discussions provided herein that analogues and derivatives of doxorubicin (as described previously) with similar functional activity can be utilized for the purposes of this invention; the above dosing parameters are then adjusted according to the relative potency of the analogue or derivative as compared to the parent compound (e.g. a compound twice as potent as doxorubicin is administered at half the above parameters, a compound half as potent as doxorubicin is administered at twice the above parameters, etc.).

[0213]

Utilizing mitoxantrone as another example of an anthracycline, whether applied as a polymer coating, incorporated into the polymers which make up the urinary catheter, or applied without a carrier polymer, the total dose of mitoxantrone applied should not exceed 5 mg (range of 0.01 μg to 5 mg). In a particularly preferred embodiment, the total amount of drug applied should be in the range of 0.1 μg to 1 mg. The dose per unit area (i.e. the amount of drug as a function of the surface area of the portion of the urinary catheter to which drug is applied and/or incorporated) should fall within the range of 0.01 μg-20 μg per mm2 of surface area. In a particularly preferred embodiment, mitoxantrone should be applied to the urinary catheter surface at a dose of 0.05 μg/mm2-3 μg/mm2. As different polymer and non-polymer coatings will release mitoxantrone at differing rates, the above dosing parameters should be utilized in combination with the release rate of the drug from the urinary catheter surface such that a minimum concentration of 10−5-10−6 M of mitoxantrone is maintained. It is necessary to insure that drug concentrations on the surface exceed concentrations of mitoxantrone known to be lethal to multiple species of bacteria and fungi (i.e. are in excess of 10−5 M; although for some embodiments lower drug levels will be sufficient). In a preferred embodiment, mitoxantrone is released from the urinary catheter surface such that anti-infective activity is maintained for a period ranging from several hours to several months. In a particularly preferred embodiment the drug is released in effective concentrations for a period ranging from 1 hour-1 month. It should be readily evident given the discussions provided herein that analogues and derivatives of mitoxantrone (as described previously) with similar functional activity can be utilized for the purposes of this invention; the above dosing parameters are then adjusted according to the relative potency of the analogue or derivative as compared to the parent compound (e.g. a compound twice as potent as mitoxantrone is administered at half the above parameters, a compound half as potent as mitoxantrone is administered at twice the above parameters, etc.).

[0214]

(b) Fluoropyrim idines Utilizing the fluoropyrimidine 5-fluorouracil as an example, whether applied as a polymer coating, incorporated into the polymers which make up the urinary catheter, or applied without a carrier polymer, the total dose of 5-fluorouracil applied should not exceed 250 mg (range of 1.0 μg to 250 mg). In a particularly preferred embodiment, the total amount of drug applied should be in the range of 10 μg to 25 mg. The dose per unit area (i.e. the amount of drug as a function of the surface area of the portion of the urinary catheter to which drug is applied and/or incorporated) should fall within the range of 0.1 μg-1 mg per mm2 of surface area. In a particularly preferred embodiment, 5-fluorouracil should be applied to the urinary catheter surface at a dose of 1.0 μg/mm2-50 μg/mm2. As different polymer and non-polymer coatings will release 5-fluorouracil at differing rates, the above dosing parameters should be utilized in combination with the release rate of the drug from the urinary catheter surface such that a minimum concentration of 10−4-10−7 M of 5-fluorouracil is maintained. It is necessary to insure that surface drug concentrations exceed concentrations of 5-fluorouracil known to be lethal to numerous species of bacteria and fungi (i.e., are in excess of 10−4 M; although for some embodiments lower drug levels will be sufficient). In a preferred embodiment, 5-fluorouracil is released from the urinary catheter surface such that anti-infective activity is maintained for a period ranging from several hours to several months. In a particularly preferred embodiment the drug is released in effective concentrations for a period ranging from 1 hour-1 month. It should be readily evident given the discussions provided herein that analogues and derivatives of 5-fluorouracil (as described previously) with similar functional activity can be utilized for the purposes of this invention; the above dosing parameters are then adjusted according to the relative potency of the analogue or derivative as compared to the parent compound (e.g. a compound twice as potent as 5-fluorouracil is administered at half the above parameters, a compound half as potent as 5-fluorouracil is administered at twice the above parameters, etc.).

[0215]

(c) Podophylotoxins Utilizing the podophylotoxin etoposide as an example, whether applied as a polymer coating, incorporated into the polymers which make up the urinary catheter, or applied without a carrier polymer, the total dose of etoposide applied should not exceed 25 mg (range of 0.1 μg to 25 mg). In a particularly preferred embodiment, the total amount of drug applied should be in the range of 1 μg to 5 mg. The dose per unit area (i.e. the amount of drug as a function of the surface area of the portion of the urinary catheter to which drug is applied and/or incorporated) should fall within the range of 0.01 μg-100 μg per mm2 of surface area. In a particularly preferred embodiment, etoposide should be applied to the urinary catheter surface at a dose of 0.1 μg/mm2-10 μg/mm2. As different polymer and non-polymer coatings will release etoposide at differing rates, the above dosing parameters should be utilized in combination with the release rate of the drug from the urinary catheter surface such that a concentration of 10−5-10−6 M of etoposide is maintained. It is necessary to insure that surface drug concentrations exceed concentrations of etoposide known to be lethal to a variety of bacteria and fungi (i.e. are in excess of 10−5 M; although for some embodiments lower drug levels will be sufficient). In a preferred embodiment, etoposide is released from the surface of the urinary catheter such that anti-infective activity is maintained for a period ranging from several hours to several months. In a particularly preferred embodiment the drug is released in effective concentrations for a period ranging from 1 hour-1 month. It should be readily evident given the discussions provided herein that analogues and derivatives of etoposide (as described previously) with similar functional activity can be utilized for the purposes of this invention; the above dosing parameters are then adjusted according to the relative potency of the analogue or derivative as compared to the parent compound (e.g. a compound twice as potent as etoposide is administered at half the above parameters, a compound half as potent as etoposide is administered at twice the above parameters, etc.).

Ureteral stents are hollow tubes with holes along the sides and coils at either end to prevent migration. Ureteral stents are used to relieve obstructions (caused by stones or malignancy), to facilitate the passage of stones, or to allow healing of ureteral anastomoses or leaks following surgery or trauma. They are placed endoscopically via the bladder or percutaneously via the kidney. A microbial biofilm forms on up to 90% of ureteral stents and 30% develop significant bacteruria with the incidence increasing the longer the stent is in place. Pseudomonas aeruginosa is the most common pathogen, but Enterococci, Staphylococcus aureus and Candida also cause infection. Effective treatment frequently requires stent removal in addition to antibiotic therapy.

[0219]

Unfortunately, ureteral stents can become infected or encrusted with urinary salts that render them ineffective. An effective ureteral stent coating would allow easy insertion, remain in place for as long as is required, be easily removed, resist infection and prevent the formation of urinary salts. Therefore, development of a ureteral stent which does not become obstructed by granulation tissue, does not scar in place and is less prone to infection would be beneficial.

[0220]

In a preferred embodiment, doxorubicin, mitoxantrone, 5-fluorouracil and/or etoposide are formulated into a coating applied to the surface of the ureteral stent. The drug(s) can be applied in several manners: (a) as a coating applied to the external surface of the ureteral stent; (b) as a coating applied to the internal (luminal) surface of the ureteral stent; (c) as a coating applied to all or parts of both surfaces; and/or (d) incorporated into the polymers which comprise the ureteral stent.

[0221]

Drug-coating of, or drug incorporation into, the ureteral stent will allow bacteriocidal drug levels to be achieved locally on the stent surface, thus reducing the incidence of bacterial colonization (and subsequent development of pyelonephritis and/or bacteremia), while producing negligible systemic exposure to the drugs. Although for some agents polymeric carriers are not required for attachment of the drug to the ureteral stent surface, several polymeric carriers are particularly suitable for use in this embodiment. Of particular interest are polymeric carriers such as polyurethanes (e.g., ChronoFlex AL 85A [CT Biomaterials], HydroMed640™ [CT Biomaterials], HYDROSLIP C™ [CT Biomaterials], HYDROTHANE™ [CT Biomaterials]), acrylic or methacrylic copolymers (e.g. poly(ethylene-co-acrylic acid), cellulose-derived polymers (e.g. nitrocellulose, Cellulose Acetate Butyrate, Cellulose acetate propionate), acrylate and methacrylate copolymers (e.g. poly(ethylene-co-vinyl acetate)) as well as blends thereof.

[0222]

As ureteral stents are prone to the same complications and infections from the same bacteria, the dosing guidelines for doxorubicin, mitoxantrone, 5-fluorouracil and etoposide in coating ureteral stents are identical to those described above for urinary catheters. However, unlike the formulations described for urinary catheters, drug release should occur over a 2 to 24 week period.

[0223]

Urethral Stents

[0224]

Urethral stents are used for the treatment of recurrent urethral strictures, detruso-external sphincter dyssynergia and bladder outlet obstruction due to benign prostatic hypertrophy. The stents are typically self-expanding and composed of metal superalloy, titanium, stainless steel or polyurethane. Infections are most often due to Coagulase Negative Staphylococci, Pseudomonas aeruginosa, Enterococci, Staphylococcus aureus, Serratia and Candida. Treatment of infected stents frequently requires systemic antibiotic therapy and removal of the device.

[0225]

An effective urethral stent coating would allow easy insertion, remain in place for as long as is required, be easily removed, resist infection and prevent the formation of urinary salts. Therefore, development of a urethral stent which does not become obstructed by granulation tissue, does not scar in place and is less prone to infection would be beneficial.

[0226]

In a preferred embodiment, doxorubicin, mitoxantrone, 5-fluorouracil and/or etoposide are formulated into a coating applied to the surface of the urethral stent. The drug(s) can be applied in several manners: (a) as a coating applied to the external surface of the urethral stent; (b) as a coating applied to the internal (luminal) surface of the urethral stent; (c) as a coating applied to all or parts of both surfaces; and/or (d) incorporated into the polymers which comprise the urethral stent.

[0227]

Drug-coating of, or drug incorporation into, the urethral stent will allow bacteriocidal drug levels to be achieved locally on the stent surface, thus reducing the incidence of bacterial colonization (and subsequent development of pyelonephritis and/or bacteremia), while producing negligible systemic exposure to the drugs. Although for some agents polymeric carriers are not required for attachment of the drug to the ureteral stent surface, several polymeric carriers are particularly suitable for use in this embodiment. Of particular interest are polymeric carriers such as polyurethanes (e.g., ChronoFlex AL 85A [CT Biomaterials], HydroMed640™ [CT Biomaterials], HYDROSLIP C™ [CT Biomaterials], HYDROTHANE™ [CT Biomaterials]), acrylic or methacrylic copolymers (e.g. poly(ethylene-co-acrylic acid), cellulose-derived polymers (e.g. nitrocellulose, Cellulose Acetate Butyrate, Cellulose acetate propionate), acrylate and methacrylate copolymers (e.g. poly(ethylene-co-vinyl acetate)) as well as blends thereof.

[0228]

As urethral stents are prone to the same complications and infections from the same bacteria, the dosing guidelines for doxorubicin, mitoxantrone, 5-fluorouracil and etoposide in coating ureteral stents are identical to those described above for urinary catheters. However, unlike the formulations described for urinary catheters, drug release should occur over a 2 to 24 week period.

[0229]

Prosthetic Bladder Sphincters

[0230]

Prosthetic bladder sphincters are used to treat incontinence and generally consist of a periurethral implant. The placement of prosthetic bladder sphincters can be complicated by infection (usually in the first 6 months after surgery) with Coagulase Negative Staphylococci (including Staphylococcus epidermidis), Staphylococcus aureus, Pseudomonas aeruginosa, Enterococci, Serratia and Candida. Infection is characterized by fever, erythema, induration and purulent drainage from the operative site. The usual route of infection is through the incision at the time of surgery and up to 3% of prosthetic bladder sphincters become infected despite the best sterile surgical technique. To help combat this, intraoperative irrigation with antibiotic solutions is often employed.

[0231]

Treatment of infections of prosthetic bladder sphincters requires complete removal of the device and antibiotic therapy; replacement of the device must often be delayed for 3-6 months after the infection has cleared. An effective prosthetic bladder sphincter coating would resist infection and reduce the incidence of re-intervention.

[0232]

In a preferred embodiment, doxorubicin, mitoxantrone, 5-fluorouracil and/or etoposide are formulated into a coating applied to the surface of the prosthetic bladder sphincter. The drug(s) can be applied in several manners: (a) as a coating applied to the external surface of the prosthetic bladder sphincter; and/or (b) incorporated into the polymers which comprise the prosthetic bladder sphincter.

As prosthetic bladder sphincters are prone to infections caused by the same bacteria as occur with urinary catheters, the dosing guidelines for doxorubicin, mitoxantrone, 5-fluorouracil and etoposide in coating prosthetic bladder sphincters are identical to those described above for urinary catheters. However, unlike the formulations described for urinary catheters, drug release should occur over a 2 to 24 week period.

[0235]

Penile Implants

[0236]

Penile implants are used to treat erectile dysfunction and are generally flexible rods, hinged rods or inflatable devices with a pump. The placement of penile implants can be complicated by infection (usually in the first 6 months after surgery) with Coagulase Negative Staphylococci (including Staphylococcus epidermidis), Staphylococcus aureus, Pseudomonas aeruginosa, Enterococci, Serratia and Candida. The type of device or route of insertion does not affect the incidence of infection. Infection is characterized by fever, erythema, induration and purulent drainage from the operative site. The usual route of infection is through the incision at the time of surgery and up to 3% of penile implants become infected despite the best sterile surgical technique. To help combat this, intraoperative irrigation with antibiotic solutions is often employed.

[0237]

Treatment of infections of penile implants requires complete removal of the device and antibiotic therapy; replacement of the device must often be delayed for 3-6 months after the infection has cleared. An effective penile implant coating would resist infection and reduce the incidence of re-intervention.

[0238]

In a preferred embodiment, doxorubicin, mitoxantrone, 5-fluorouracil and/or etoposide are formulated into a coating applied to the surface of the penile implant. The drug(s) can be applied in several manners: (a) as a coating applied to the external surface of the penile implant; and/or (b) incorporated into the polymers which comprise the penile implant.

[0239]

Drug-coating of, or drug incorporation into, the penile implant will allow bacteriocidal drug levels to be achieved locally, thus reducing the incidence of bacterial colonization (and subsequent development of local infection and device failure), while producing negligible systemic exposure to the drugs. Although for some agents polymeric carriers are not required for attachment of the drug to the penile implant surface, several polymeric carriers are particularly suitable for use in this embodiment.

[0240]

As penile implants are prone to infections caused by the same bacteria as occur with urinary catheters, the dosing guidelines for doxorubicin, mitoxantrone, 5-fluorouracil and etoposide in coating penile implants are identical to those described above for urinary catheters. However, unlike the formulations described for urinary catheters, drug release should occur over a 2 to 24 week period.

H. Infections Associated with Endotracheal and Tracheostomy Tubes

[0241]

Endotracheal tubes and tracheostomy tubes are used to maintain the airway when ventilatory assistance is required. Endotracheal tubes tend to be used to establish an airway in the acute setting, while tracheostomy tubes are used when prolonged ventilation is required or when there is a fixed obstruction in the upper airway. In hospitalized patients, nosocomial pneumonia occurs 300,000 times per year and is the second most common cause of hospital-acquired infection (after urinary tract infection) and the most common infection in ICU patients. In the intensive care unit, nosocomial pneumonia is a frequent cause death with fatality rates over 50%. Survivors spend on average 2 weeks longer in hospital and the annual cost of treatment is close to $2 billion.

[0242]

Bacterial pneumonia is the most common cause of excess morbidity and mortality in patients who require intubation. In patients who are intubated electively (i.e. for elective surgery), less than 1% will develop a nosocomial pneumonia. However, patients who are severely ill with ARDS (Adult Respiratory Distress Syndrome) have a greater than 50% chance of developing a nosocomial pneumonia. It is thought that new organisms colonize the oropharynx in intubated patients, are swallowed to contaminate the stomach, are aspirated to inoculate the lower airway and eventually contaminate the endotracheal tube. Bacteria adhere to the tube, form a biolayer and multiply serving as a source for bacteria that can aerosolize and be carried distally into the lungs. Chronic tracheostomy tubes also frequently become colonized with pathogenic bacteria known to cause pneumonia. The most common causes of pneumonia in ventilated patients are Staphylococcus aureus (17%), Pseudomonas aeruginosa (18%), Klebsiella pneumoniae (9%), Enterobacter (9%) and Haemophilus influenza (5%). Treatment requires aggressive therapy with antibiotics.

[0243]

An effective endotracheal tube or tracheostomy tube coating would resist infection and prevent the formation of biofilm in the tube. An effective coating would prevent or reduce the incidence of pneumonia, sepsis and death. In a preferred embodiment, doxorubicin, mitoxantrone, 5-fluorouracil and/or etoposide are formulated into a coating applied to the surface of the endotracheal tube or tracheostomy tube. Due to its activity against Klebsiella pneumoniae, methotrexate can also be useful for this embobiment. As cisplatin and hydroxyurea have some activity against Pseudomonas aeruginosa, they can also be of some utility in the practice of this embodiment. The drug(s) can be applied in several manners: (a) as a coating applied to the external surface of the endotracheal tube or tracheostomy tube; (b) as a coating applied to the internal (luminal) surface of the endotracheal tube or tracheostomy tube; (c) as a coating applied to all or parts of both surfaces; and/or (d) incorporated into the polymers which comprise the endotracheal tube or tracheostomy tube.

[0244]

Drug-coating of, or drug incorporation into, the endotracheal tube or tracheostomy tube will allow bacteriocidal drug levels to be achieved locally on the catheter surface, thus reducing the incidence of bacterial colonization (and subsequent development of pneumonia and sepsis), while producing negligible systemic exposure to the drugs. Although for some agents polymeric carriers are not required for attachment of the drug to the endotracheal tube or tracheostomy tube surface, several polymeric carriers are particularly suitable for use in this embodiment. Of particular interest are polymeric carriers such as polyurethanes (e.g., ChronoFlex AL 85A [CT Biomaterials], HydroMed640™ [CT Biomaterials], HYDROSLIP C™ [CT Biomaterials], HYDROTHANE™ [CT Biomaterials]), acrylic or methacrylic copolymers (e.g. poly(ethylene-co-acrylic acid), cellulose-derived polymers (e.g. nitrocellulose, Cellulose Acetate Butyrate, Cellulose acetate propionate), acrylate and methacrylate copolymers (e.g. poly(ethylene-co-vinyl acetate)) as well as blends thereof.

[0245]

As endotracheal tube and tracheostomy tubes are made in a variety of configurations and sizes, the exact dose administered will vary with device size, surface area and design. However, certain principles can be applied in the application of this art. Drug dose can be calculated as a function of dose per unit area (of the portion of the device being coated), total drug dose administered can be measured and appropriate surface concentrations of active drug can be determined. Regardless of the method of application of the drug to the endotracheal tube or tracheostomy tube, the preferred anticancer agents, used alone or in combination, should be administered under the following dosing guidelines:

[0246]

(a) Anthracyclines. Utilizing the anthracycline doxorubicin as an example, whether applied as a polymer coating, incorporated into the polymers which make up the endotracheal tube or tracheostomy tube components, or applied without a carrier polymer, the total dose of doxorubicin applied should not exceed 25 mg (range of 0.1 μg to 25 mg). In a particularly preferred embodiment, the total amount of drug applied should be in the range of 1 μg to 5 mg. The dose per unit area (i.e. the amount of drug as a function of the surface area of the portion of the endotracheal tube or tracheostomy tube to which drug is applied and/or incorporated) should fall within the range of 0.01 μg-100 μg per mm2 of surface area. In a particularly preferred embodiment, doxorubicin should be applied to the endotracheal tube or tracheostomy tube surface at a dose of 0.1 μg/mm2-10 μg/mm2. As different polymer and non-polymer coatings will release doxorubicin at differing rates, the above dosing parameters should be utilized in combination with the release rate of the drug from the endotracheal tube or tracheostomy tube surface such that a minimum concentration of 10−7-10−4 M of doxorubicin is maintained on the surface. It is necessary to insure that surface drug concentrations exceed concentrations of doxorubicin known to be lethal to multiple species of bacteria and fungi (i.e., are in excess of 10−4M; although for some embodiments lower concentrations are sufficient). In a preferred embodiment, doxorubicin is released from the surface of the endotracheal tube or tracheostomy tube such that anti-infective activity is maintained for a period ranging from several hours to several months. In a particularly preferred embodiment the drug is released in effective concentrations from the endotracheal tube for a period ranging from 1 hour to 1 month, while release from a tracheostomy tube would range from 1 day to 3 months. It should be readily evident given the discussions provided herein that analogues and derivatives of doxorubicin (as described previously) with similar functional activity can be utilized for the purposes of this invention; the above dosing parameters are then adjusted according to the relative potency of the analogue or derivative as compared to the parent compound (e.g. a compound twice as potent as doxorubicin is administered at half the above parameters, a compound half as potent as doxorubicin is administered at twice the above parameters, etc.).

[0247]

Utilizing mitoxantrone as another example of an anthracycline, whether applied as a polymer coating, incorporated into the polymers which make up the endotracheal tube or tracheostomy tube, or applied without a carrier polymer, the total dose of mitoxantrone applied should not exceed 5 mg (range of 0.01 μg to 5 mg). In a particularly preferred embodiment, the total amount of drug applied should be in the range of 0.1 μg to 1 mg. The dose per unit area (i.e. the amount of drug as a function of the surface area of the portion of the endotracheal tube or tracheostomy tube to which drug is applied and/or incorporated) should fall within the range of 0.01 μg-20 μg per mm2 of surface area. In a particularly preferred embodiment, mitoxantrone should be applied to the endotracheal tube or tracheostomy tube surface at a dose of 0.05 μg/mm2-3 μg/mm2. As different polymer and non-polymer coatings will release mitoxantrone at differing rates, the above dosing parameters should be utilized in combination with the release rate of the drug from the endotracheal tube or tracheostomy tube surface such that a minimum concentration of 10−5-10−6 M of mitoxantrone is maintained. It is necessary to insure that drug concentrations on the surface exceed concentrations of mitoxantrone known to be lethal to multiple species of bacteria and fungi (i.e. are in excess of 10−5 M; although for some embodiments lower drug levels will be sufficient). In a preferred embodiment, mitoxantrone is released from the endotracheal tube or tracheostomy tube surface such that anti-infective activity is maintained for a period ranging from several hours to several months. In a particularly preferred embodiment, the drug is released in effective concentrations from the endotracheal tube for a period ranging from 1 hour to 1 month, while release from a tracheostomy tube would range from 1 day to 3 months. It should be readily evident given the discussions provided herein that analogues and derivatives of mitoxantrone (as described previously) with similar functional activity can be utilized for the purposes of this invention; the above dosing parameters are then adjusted according to the relative potency of the analogue or derivative as compared to the parent compound (e.g. a compound twice as potent as mitoxantrone is administered at half the above parameters, a compound half as potent as mitoxantrone is administered at twice the above parameters, etc.).

[0248]

(b) Fluoropyrimidines Utilizing the fluoropyrimidine 5-fluorouracil as an example, whether applied as a polymer coating, incorporated into the polymers which make up the endotracheal tube or tracheostomy tube, or applied without a carrier polymer, the total dose of 5-fluorouracil applied should not exceed 250 mg (range of 1.0 μg to 250 mg). In a particularly preferred embodiment, the total amount of drug applied should be in the range of 10 μg to 25 mg. The dose per unit area (i.e. the amount of drug as a function of the surface area of the portion of the endotracheal tube or tracheostomy tube to which drug is applied and/or incorporated) should fall within the range of 0.1 μg-1 mg per mm2 of surface area. In a particularly preferred embodiment, 5-fluorouracil should be applied to the endotracheal tube or tracheostomy tube surface at a dose of 1.0 μg/mm2-50 μg/mm2. As different polymer and non-polymer coatings will release 5-fluorouracil at differing rates, the above dosing parameters should be utilized in combination with the release rate of the drug from the endotracheal tube or tracheostomy tube surface such that a minimum concentration of 10−4-10−7 M of 5-fluorouracil is maintained. It is necessary to insure that surface drug concentrations exceed concentrations of 5-fluorouracil known to be lethal to numerous species of bacteria and fungi (i.e. are in excess of 10−4 M; although for some embodiments lower drug levels will be sufficient). In a preferred embodiment, 5-fluorouracil is released from the endotracheal tube or tracheostomy tube surface such that anti-infective activity is maintained for a period ranging from several hours to several months. In a particularly preferred embodiment, the drug is released in effective concentrations from the endotracheal tube for a period ranging from 1 hour to 1 month, while release from a tracheostomy tube would range from 1 day to 3 months. It should be readily evident given the discussions provided herein that analogues and derivatives of 5-fluorouracil (as described previously) with similar functional activity can be utilized for the purposes of this invention; the above dosing parameters are then adjusted according to the relative potency of the analogue or derivative as compared to the parent compound (e.g. a compound twice as potent as 5-fluorouracil is administered at half the above parameters, a compound half as potent as 5-fluorouracil is administered at twice the above parameters, etc.).

[0249]

(c) Podophylotoxins Utilizing the podophylotoxin etoposide as an example, whether applied as a polymer coating, incorporated into the polymers which make up the endotracheal tube or tracheostomy tube, or applied without a carrier polymer, the total dose of etoposide applied should not exceed 25 mg (range of 0.1 μg to 25 mg). In a particularly preferred embodiment, the total amount of drug applied should be in the range of 1 μg to 5 mg. The dose per unit area (i.e. the amount of drug as a function of the surface area of the portion of the endotracheal tube or tracheostomy tube to which drug is applied and/or incorporated) should fall within the range of 0.01 μg-100 μg per mm2 of surface area. In a particularly preferred embodiment, etoposide should be applied to the endotracheal tube or tracheostomy tube surface at a dose of 0.1 μg/mm2-10 μg/mm2. As different polymer and non-polymer coatings will release etoposide at differing rates, the above dosing parameters should be utilized in combination with the release rate of the drug from the endotracheal tube or tracheostomy tube surface such that a concentration of 10−5-10−6 M of etoposide is maintained. It is necessary to insure that surface drug concentrations exceed concentrations of ptoposide known to be lethal to a variety of bacteria and fungi (i.e. are in excess of 10−5 M; although for some embodiments lower drug levels will be sufficient). In a preferred embodiment, etoposide is released from the surface of the endotracheal tube or tracheostomy tube such that anti-infective activity is maintained for a period ranging from several hours to several months. In a particularly preferred, embodiment the drug is released in effective concentrations from the endotracheal tube for a period ranging from 1 hour to 1 month, while release from a tracheostomy tube would range from 1 day to 3 months. It should be readily evident given the discussions provided herein that analogues and derivatives of etoposide (as described previously) with similar functional activity can be utilized for the purposes of this invention; the above dosing parameters are then adjusted according to the relative potency of the analogue or derivative as compared to the parent compound (e.g. a compound twice as potent as etoposide is administered at half the above parameters, a compound half as potent as etoposide is administered at twice the above parameters, etc.).

In 1997, there were over 300,000 patients in the United States with end-stage renal disease. Of these, 63% were treated with hemodialysis, 9% with peritoneal dialysis and 38% with renal transplantation. Hemodialysis requires reliable access to the vascular system typically as a surgically created arteriovenous fistula (AVF; 18%), via a synthetic bridge graft (usually a PTFE arteriovenous interposition graft in the forearm or leg; 50%) or a central venous catheter (32%). Peritoneal dialysis requires regular exchange of dialysate through the peritoneum via a double-cuffed and tunnelled peritoneal dialysis catheter. Regardless of the form of dialysis employed, infection is the second leading cause of death in renal failure patients (15.5% of all deaths) after heart disease. A significant number of those infections are secondary to the dialysis procedure itself.

[0252]

Hemodialysis Access Grafts

[0253]

Kidney failure patients have a dysfunctional immune response that makes them particularly susceptible to infection. Infections of hemodialysis access grafts are characterized as either being early (within month; thought to be a complication of surgery) and late (after 1 month; thought to be related to access care). Over a 2 year period, approximately 2% of AVF's become infected while 11-16% of PTFE grafts will become infected on at least one occasion. Although infection can result from extension of an infection from an adjacent contaminated tissue or hematogenous seeding, the most common cause of infection is intraoperative contamination. The most common causes of infection include Staphylococcus aureus, Enterobacteriaceae, Pseudomonas aerugenosa, and Coagulase Negative Staphylococci.

In a preferred embodiment, doxorubicin, mitoxantrone, 5-fluorouracil and/or etoposide are formulated into a coating applied to the surface of the components of the synthetic hemodialysis access graft. The drug(s) can be applied in several manners: (a) as a coating applied to the external surface of the graft; (b) as a coating applied to the internal (luminal) surface of the graft; and/or (c) as a coating applied to all or parts of both surfaces. For an AVF, the drug would be formulated into a surgical implant placed around the outside of the fistula at the time of surgery.

[0256]

Drug-coating of, or drug incorporation into hemodialysis access grafts will allow bacteriocidal drug levels to be achieved locally on the graft surface, thus reducing the incidence of bacterial colonization and subsequent development of infectious complications, while producing negligible systemic exposure to the drugs. Although for some agents polymeric carriers are not required for attachment of the drug, several polymeric carriers are particularly suitable for use in this embodiment. Of particular interest are polymeric carriers such as polyurethanes (e.g., ChronoFlex AL 85A [CT Biomaterials], HydroMed640™ [CT Biomaterials], HYDROSLIP C™ [CT Biomaterials], HYDROTHANE™ [CT Biomaterials]), acrylic or methacrylic copolymers (e.g. poly(ethylene-co-acrylic acid), cellulose-derived polymers (e.g. nitrocellulose, Cellulose Acetate Butyrate, Cellulose acetate propionate), acrylate and methacrylate copolymers (e.g. poly(ethylene-co-vinyl acetate)) , collagen, PLG as well as blends thereof.

[0257]

An effective hemodialysis access graft coating would reduce the incidence of complications such as sepsis, haemorrhage, thrombosis, embolism, endocarditis, osteomyelitis and even death. An effective coating would also decrease the number of hemodialysis access grafts requiring replacement, resulting in lower mortality and morbidity for patients with these implants.

[0258]

As hemodialysis access grafts are made in a variety of configurations and sizes, the exact dose administered will vary with device size, surface area, design and portions of the graft coated. However, certain principles can be applied in the application of this art. Drug dose can be calculated as a function of dose per unit area (of the portion of the device being coated), total drug dose administered can be measured and appropriate surface concentrations of active drug can be determined. Regardless of the method of application of the drug to the hemodialysis access graft, the preferred anticancer agents, used alone or in combination, should be administered under the following dosing guidelines:

[0259]

(a) Anthracyclines. Utilizing the anthracycline doxorubicin as an example, whether applied as a polymer coating, incorporated into the polymers which make up the hemodialysis access graft components (such as Dacron or Teflon), or applied without a carrier polymer, the total dose of doxorubicin applied should not exceed 25 mg (range of 0.1 μg to 25 mg). In a particularly preferred embodiment, the total amount of drug applied should be in the range of 1 μg to 5 mg. The dose per unit area (i.e. the amount of drug as a function of the surface area of the portion of the hemodialysis access graft to which drug is applied and/or incorporated) should fall within the range of 0.01 μg-100 μg per mm2 of surface area. In a particularly preferred embodiment, doxorubicin should be applied to the hemodialysis access graft surface at a dose of 0.1 μg/mm2-10 μg/mm2. As different polymer and non-polymer coatings will release doxorubicin at differing rates, the above dosing parameters should be utilized in combination with the release rate of the drug from the hemodialysis access graft surface such that a minimum concentration of 10−7 -10−4 M of doxorubicin is maintained on the surface. It is necessary to insure that surface drug concentrations exceed concentrations of doxorubicin known to be lethal to multiple species of bacteria and fungi (i.e., are in excess of 10−4 M; although for some embodiments lower concentrations are sufficient). In a preferred embodiment, doxorubicin is released from the surface of the hemodialysis access graft such that anti-infective activity is maintained for a period ranging from several hours to several months. In a particularly preferred embodiment the drug is released in effective concentrations for a period ranging from 1 week-6 months. It should be readily evident given the discussions provided herein that analogues and derivatives of doxorubicin (as described previously) with similar functional activity can be utilized for the purposes of this invention; the above dosing parameters are then adjusted according to the relative potency of the analogue or derivative as compared to the parent compound (e.g. a compound twice as potent as doxorubicin is administered at half the above parameters, a compound half as potent as doxorubicin is administered at twice the above parameters, etc.).

[0260]

Utilizing mitoxantrone as another example of an anthracycline, whether applied as a polymer coating, incorporated into the polymers which make up the hemodialysis access graft (such as Dacron or Teflon), or applied without a carrier polymer, the total dose of mitoxantrone applied should not exceed 5 mg (range of 0.01 μg to 5 mg). In a particularly preferred embodiment, the total amount of drug applied should be in the range of 0.1 μg to 1 mg. The dose per unit area (i.e. the amount of drug as a function of the surface area of the portion of the hemodialysis access graft to which drug is applied and/or incorporated) should fall within the range of 0.01 μg-20 μg per mm2 of surface area. In a particularly preferred embodiment, mitoxantrone should be applied to the hemodialysis access graft surface at a dose of 0.05 μg/mm2-3 μg/mm2. As different polymer and non-polymer coatings will release mitoxantrone at differing rates, the above dosing parameters should be utilized in combination with the release rate of the drug from the hemodialysis access graft surface such that a minimum concentration of 10−5-10−6 M of mitoxantrone is maintained. It is necessary to insure that drug concentrations on the surface exceed concentrations of mitoxantrone known to be lethal to multiple species of bacteria and fungi (i.e. are in excess of 10−5 M; although for some embodiments lower drug levels will be sufficient). In a preferred embodiment, mitoxantrone is released from the hemodialysis access graft surface such that anti-infective activity is maintained for a period ranging from several hours to several months. In a particularly preferred embodiment the drug is released in effective concentrations for a period ranging from 1 week-6 months. It should be readily evident given the discussions provided herein that analogues and derivatives of mitoxantrone (as described previously) with similar functional activity can be utilized for the purposes of this invention; the above dosing parameters are then adjusted according to the relative potency of the analogue or derivative as compared to the parent compound (e.g. a compound twice as potent as mitoxantrone is administered at half the above parameters, a compound half as potent as mitoxantrone is administered at twice the above parameters, etc.).

[0261]

(b) Fluoropyrimidines Utilizing the fluoropyrimidine 5-fluorouracil as an example, whether applied as a polymer coating, incorporated into the polymers which make up the hemodialysis access graft (such as Dacron or Teflon), or applied without a carrier polymer, the total dose of 5-fluorouracil applied should not exceed 250 mg (range of 1.0 μg to 250 mg). In a particularly preferred embodiment, the total amount of drug applied should be in the range of 10 μg to 25 mg. The dose per unit area (i.e. the amount of drug as a function of the surface area of the portion of the hemodialysis access graft to which drug is applied and/or incorporated) should fall within the range of 0.1 μg-1 mg per mm2 of surface area. In a particularly preferred embodiment, 5-fluorouracil should be applied to the hemodialysis access graft surface at a dose of 1.0 μg/mm2-50 μg/mm2. As different polymer and non-polymer coatings will release 5-fluorouracil at differing rates, the above dosing parameters should be utilized in combination with the release rate of the drug from the hemodialysis access graft surface such that a minimum concentration of 10−4-10−7 M of 5-fluorouracil is maintained. It is necessary to insure that surface drug concentrations exceed concentrations of 5-fluorouracil known to be lethal to numerous species of bacteria and fungi (i.e., are in excess of 10−4 M; although for some embodiments lower drug levels will be sufficient). In a preferred embodiment, 5-fluorouracil is released from the hemodialysis access graft surface such that anti-infective activity is maintained for a period ranging from several hours to several months. In a particularly preferred embodiment the drug is released in effective concentrations for a period ranging from 1 week-6 months. It should be readily evident given the discussions provided herein that analogues and derivatives of 5-fluorouracil (as described previously) with similar functional activity can be utilized for the purposes of this invention; the above dosing parameters are then adjusted according to the relative potency of the analogue or derivative as compared to the parent compound (e.g. a compound twice as potent as 5-fluorouracil is administered at half the above parameters, a compound half as potent as 5-fluorouracil is administered at twice the above parameters, etc.).

[0262]

(c) Podophylotoxins Utilizing the podophylotoxin etoposide as an example, whether applied as a polymer coating, incorporated into the polymers which make up the hemodialysis access graft (such as Dacron or Teflon), or applied without a carrier polymer, the total dose of etoposide applied should not exceed 25 mg (range of 0.1 μg to 25 mg). In a particularly preferred embodiment, the total amount of drug applied should be in the range of 1 μg to 5 mg. The dose per unit area (i.e. the amount of drug as a function of the surface area of the portion of the hemodialysis access graft to which drug is applied and/or incorporated) should fall within the range of 0.01 μg-100 μg per mm2 of surface area. In a particularly preferred embodiment, etoposide should be applied to the hemodialysis access graft surface at a dose of 0.1 μg/mm2-10 μg/mm2. As different polymer and non-polymer coatings will release etoposide at differing rates, the above dosing parameters should be utilized in combination with the release rate of the drug from the hemodialysis access graft surface such that a concentration of 10−5-10−6 M of etoposide is maintained. It is necessary to insure that surface drug concentrations exceed concentrations of etoposide known to be lethal to a variety of bacteria and fungi (i.e. are in excess of 10−5 M; although for some embodiments lower drug levels will be sufficient). In a preferred embodiment, etoposide is released from the surface of the hemodialysis access graft such that anti-infective activity is maintained for a period ranging from several hours to several months. In a particularly preferred embodiment the drug is released in effective concentrations for a period ranging from 1 week-6 months. It should be readily evident given the discussions provided herein that analogues and derivatives of etoposide (as described previously) with similar functional activity can be utilized for the purposes of this invention; the above dosing parameters are then adjusted according to the relative potency of the analogue or derivative as compared to the parent compound (e.g. a compound twice as potent as etoposide is administered at half the above parameters, a compound half as potent as etoposide is administered at twice the above parameters, etc.).

A variety of central venous catheters are available for use in hemodialysis including, but not restricted to, catheters which are totally implanted such as the Lifesite (Vasca Inc., Tewksbury, Mass.) and the Dialock (Biolink Corp., Middleboro, Mass.). Central venous catheters are, prone to infection and embodiments for that purpose are described above.

[0266]

Peritoneal Dialysis Catheters

[0267]

Peritoneal dialysis catheters are typically double-cuffed and tunnelled catheters that provide access to the peritoneum. The most common peritoneal dialysis catheter designs are the Tenckhoff catheter, the Swan Neck Missouri catheter and the Toronto Western catheter. In peritoneal dialysis, the peritoneum acts as a semipermeable membrane across which solutes can be exchanged down a concentration gradient.

[0268]

Peritoneal dialysis infections are typically classified as either peritonitis or exit-site/tunnel infections (i.e. catheter infections). Exit-site/tunnel infections are characterized by redness, induration or purulent discharge from the exit site or subcutaneous portions of the catheter. Peritonitis is more a severe infection that causes abdominal pain, nausea, fever and systemic evidence of infection. Unfortunately, the peritoneal dialysis catheter likely plays a role in both types of infection. In exit-site/tunnel infections, the catheter itself becomes infected. In peritonitis, the infection is frequently the result of bacteria tracking from the skin through the catheter lumen or migrating on the outer surface (pericatheter route) of the catheter into the peritoneum. Peritoneal catheter-related infections are typically caused by Staphylococcus aureus, Coagulase Negative Staphylococci, Escherichia coli, Viridans group streptococci, Enterobacteriacae, Corynebacterium, Branhamella, Actinobacter, Serratia, Proteus, Pseudomonas aeruginosa and Fungi.

[0269]

Treatment of peritonitis involves rapid in-and-out exchanges of dialysate, systemic antibiotics (intravenous and/or intraperitoneal administration) and often requires removal of the catheter. Complications include hospitalization, the need to switch to another form of dialysis (30%) and mortality (2%; higher if the infection is due to Enterococci, S. aureus or polymicrobial).

[0270]

In a preferred embodiment, doxorubicin, mitoxantrone, 5-fluorouracil and/or etoposide are formulated into a coating applied to the surface of the components of the synthetic peritoneal dialysis graft. The drug(s) can be applied in several manners: (a) as a coating applied to the external surface of the graft; (b) as a coating applied to the internal (luminal) surface of the graft; (c) as a coating applied to the superficial cuff; (d) as a coating applied to the deep cuff; (e) incorporated into the polymers that comprise the graft; and/or (f) as a coating applied to a combination of these surfaces.

[0271]

Drug-coating of, or drug incorporation into peritoneal dialysis grafts will allow bacteriocidal drug levels to be achieved locally on the graft surface, thus reducing the incidence of bacterial colonization and subsequent development of infectious complications, while producing negligible systemic exposure to the drugs. Although for some agents polymeric carriers are not required for attachment of the drug, several polymeric carriers are particularly suitable for use in this embodiment. Of particular interest are polymeric carriers such as polyurethanes (e.g., ChronoFlex AL 85A [CT Biomaterials], HydroMed640™ [CT Biomaterials], HYDROSLIP C™ [CT Biomaterials], HYDROTHANE™ [CT Biomaterials]), acrylic or methacrylic copolymers (e.g. poly(ethylene-co-acrylic acid), cellulose-derived polymers (e.g. nitrocellulose, Cellulose Acetate Butyrate, Cellulose acetate propionate), acrylate and methacrylate copolymers (e.g. poly(ethylene-co-vinyl acetate)) as well as blends thereof.

[0272]

An effective peritoneal dialysis graft coating would reduce the incidence of complications such as hospitalization, peritonoitis, sepsis, and even death. An effective coating would also decrease the number of peritoneal dialysis grafts requiring replacement, resulting in lower mortality and morbidity for patients with these implants.

[0273]

As peritoneal dialysis grafts are made in a variety of configurations and sizes, the exact dose administered will vary with device size, surface area, design and portions of the graft coated. However, certain principles can be applied in the application of this art. Drug dose can be calculated as a function of dose per unit area (of the portion of the device being coated), total drug dose administered can be measured and appropriate surface concentrations of active drug can be determined. Regardless of the method of application of the drug to the peritoneal dialysis graft, the preferred anticancer agents, used alone or in combination, should be administered under the following dosing guidelines:

[0274]

(a) Anthracyclines. Utilizing the anthracycline doxorubicin as an example, whether applied as a polymer coating, incorporated into the polymers which make up the peritoneal dialysis graft components (such as Dacron or Teflon), or applied without a carrier polymer, the total dose of doxorubicin applied should not exceed 25 mg (range of 0.1 μg to 25 mg). In a particularly preferred embodiment, the total amount of drug applied should be in the range of 1 μg to 5 mg. The dose per unit area (i.e. the amount of drug as a function of the surface area of the portion of the peritoneal dialysis graft to which drug is applied and/or incorporated) should fall within the range of 0.01 μg-100 μg per mm2 of surface area. In a particularly preferred embodiment, doxorubicin should be applied to the peritoneal dialysis graft surface at a dose of 0.1 μg/mm2-10 μg/mm2. As different polymer and non-polymer coatings will release doxorubicin at differing rates, the above dosing parameters should be utilized in combination with the release rate of the drug from the peritoneal dialysis graft surface such that a minimum concentration of 10−7-10−4 M of doxorubicin is maintained on the surface. It is necessary to insure that surface drug concentrations exceed concentrations of doxorubicin known to be lethal to multiple species of bacteria and fungi (i.e., are in excess of 10−4M; although for some embodiments lower concentrations are sufficient). In a preferred embodiment, doxorubicin is released from the surface of the peritoneal dialysis graft such that anti-infective activity is maintained for a period ranging from several hours to several months. In a particularly preferred embodiment the drug is released in effective concentrations for a period ranging from 1 week-6 months. It should be readily evident given the discussions provided herein that analogues and derivatives of doxorubicin (as described previously) with similar functional activity can be utilized for the purposes of this invention; the above dosing parameters are then adjusted according to the relative potency of the analogue or derivative as compared to the parent compound (e.g. a compound twice as potent as doxorubicin is administered at half the above parameters, a compound half as potent as doxorubicin is administered at twice the above parameters, etc.).

[0275]

Utilizing mitoxantrone as another example of an anthracycline, whether applied as a polymer coating, incorporated into the polymers which make up the peritoneal dialysis graft (such as Dacron or Teflon), or applied without a carrier polymer, the total dose of mitoxantrone applied should not exceed 5 mg (range of 0.01 μg to 5 mg). In a particularly preferred embodiment, the total amount of drug applied should be in the range of 0.1 μg to 1 mg. The dose per unit area (i.e. the amount of drug as a function of the surface area of the portion of the peritoneal dialysis graft to which drug is applied and/or incorporated) should fall within the range of 0.01 μg-20 μg per mm2 of surface area. In a particularly preferred embodiment, mitoxantrone should be applied to the peritoneal dialysis graft surface at a dose of 0.05 μg/mm2-3 μg/mm2. As different polymer and non-polymer coatings will release mitoxantrone at differing rates, the above dosing parameters should be utilized in combination with the release rate of the drug from the peritoneal dialysis graft surface such that a minimum concentration of 10−5-10−6 M of mitoxantrone is maintained. It is necessary to insure that drug concentrations on the surface exceed concentrations of mitoxantrone known to be lethal to multiple species of bacteria and fungi (i.e. are in excess of 10−5 M; although for some embodiments lower drug levels will be sufficient). In a preferred embodiment, mitoxantrone is released from the peritoneal dialysis graft surface such that anti-infective activity is maintained for a period ranging from several hours to several months. In a particularly preferred embodiment the drug is released in effective concentrations for a period ranging from 1 week-6 months. It should be readily evident given the discussions provided herein that analogues and derivatives of mitoxantrone (as described previously) with similar functional activity can be utilized for the purposes of this invention; the above dosing parameters are then adjusted according to the relative potency of the analogue or derivative as compared to the parent compound (e.g. a compound twice as potent as mitoxantrone is administered at half the above parameters, a compound half as potent as mitoxantrone is administered at twice the above parameters, etc.).

[0276]

(b) Fluoropyrimidines Utilizing the fluoropyrimidine 5-fluorouracil as an example, whether applied as a polymer coating, incorporated into the polymers which make up the peritoneal dialysis graft (such as Dacron or Teflon), or applied without a carrier polymer, the total dose of 5-fluorouracil applied should not exceed 250 mg (range of 1.0 μg to 250 mg). In a particularly preferred embodiment, the total amount of drug applied should be in the range of 10 μg to 25 mg. The dose per unit area (i.e. the amount of drug as a function of the surface area of the portion of the peritoneal dialysis graft to which drug is applied and/or incorporated) should fall within the range of 0.1 μg-1 mg per mm2 of surface area. In a particularly preferred embodiment, 5-fluorouracil should be applied to the peritoneal dialysis graft surface at a dose of 1.0 μg/mm2-50 μg/mm2. As different polymer and non-polymer coatings will release 5-fluorouracil at differing rates, the above dosing parameters should be utilized in combination with the release rate of the drug from the peritoneal dialysis graft surface such that a minimum concentration of 10−4-10−7 M of 5-fluorouracil is maintained. It is necessary to insure that surface drug concentrations exceed concentrations of 5-fluorouracil known to be lethal to numerous species of bacteria and fungi (i.e., are in excess of 10−4 M; although for some embodiments lower drug levels will be sufficient). In a preferred embodiment, 5-fluorouracil is released from the peritoneal dialysis graft surface such that anti-infective activity is maintained for a period ranging from several hours to several months. In a particularly preferred embodiment the drug is released in effective concentrations for a period ranging from 1 week-6 months. It should be readily evident given the discussions provided herein that analogues and derivatives of 5-fluorouracil (as described previously) with similar functional activity can be utilized for the purposes of this invention; the above dosing parameters are then adjusted according to the relative potency of the analogue or derivative as compared to the parent compound (e.g. a compound twice as potent as 5-fluorouracil is administered at half the above parameters, a compound half as potent as 5-fluorouracil is administered at twice the above parameters, etc.).

[0277]

(c) Podophylotoxins Utilizing the podophylotoxin etoposide as an example, whether applied as a polymer coating, incorporated into the polymers which make up the peritoneal dialysis graft (such as Dacron or Teflon), or applied without a carrier polymer, the total dose of etoposide applied should not exceed 25 mg (range of 0.1 μg to 25 mg). In a particularly preferred embodiment, the total amount of drug applied should be in the range of 1 μg to 5 mg. The dose per unit area (i.e. the amount of drug as a function of the surface area of the portion of the peritoneal dialysis graft to which drug is applied and/or incorporated) should fall within the range of 0.01 μg-100 μg per mm2 of surface area. In a particularly preferred embodiment, etoposide should be applied to the peritoneal dialysis graft surface at a dose of 0.1 μg/mm2-10 μg/mm2. As different polymer and non-polymer coatings will release etoposide at differing rates, the above dosing parameters should be utilized in combination with the release rate of the drug from the peritoneal dialysis graft surface such that a concentration of 10−5-10−6 M of etoposide is maintained. It is necessary to insure that surface drug concentrations exceed concentrations of etoposide known to be lethal to a variety of bacteria and fungi (i.e. are in excess of 10−5 M; although for some embodiments lower drug levels will be sufficient). In a preferred embodiment, etoposide is released from the surface of the peritoneal dialysis graft such that anti-infective activity is maintained for a period ranging from several hours to several months. In a particularly preferred embodiment the drug is released in effective concentrations for a period ranging from 1 week-6 months. It should be readily evident given the discussions provided herein that analogues and derivatives of etoposide (as described previously) with similar functional activity can be utilized for the purposes of this invention; the above dosing parameters are then adjusted according to the relative potency of the analogue or derivative as compared to the parent compound (e.g. a compound twice as potent as etoposide is administered at half the above parameters, a compound half as potent as etoposide is administered at twice the above parameters, etc.).

Hydocephalus, or accumulation of cerebrospinal fluid (CSF) in the brain, is a frequently encountered neurosurgical condition arising from congenital malformations, infection, hemmorrhage, or malignancy. The incompressible fluid exerts pressure on the brain leading to brain damage or even death if untreated. CNS shunts are conduits placed in the ventricles of the brain to divert the flow of CSF from the brain to other body compartments and relieve the fluid pressure. Ventricular CSF is diverted via a prosthetic shunt to a number of drainage locations including the pleura (ventriculopleural shunt), jugular vein, vena cava (VA shunt), gallbladder and peritoneum (VP shunt; most common).

[0280]

Unfortunately, CSF shunts are relatively prone to developing infection, although the incidence has declined from 25% twenty years ago to 10% at present as a result of improved surgical technique. Approximately 25% of all shunt complications are due to the development of infection of the shunt and these can lead to significant clinical problems such as ventriculitis, ventricular compartmentalization, meningitis, subdural empyema, nephritis (with VA shunts), seizures, cortical mantle thinning, mental retardation or death. Most infections present with fever, nausea, vomiting, malaise, or signs of increased intracranial pressure such as headache or altered consciousness. The most common organisms causing CNS shunt infections are Coagulase Negative Staphylococci (67%; Staphylococcus epidermidis is the most frequently isolated organism), Staphylococcus aureus (10-20%), viridans streptococci, Streptococcus pyogenes, Enterococcus, Corynebacterium, Escherichia coli, Klebsiella, Proteus and Pseudomonas aeruginosa. It is thought that the majority of infections are due to inoculation of the organism during surgery, or during manipulation of the shunt in the postoperative period. As a result, most infections present clinically in the first few weeks following surgery.

[0281]

Since many of the infections are caused by S. epidermidis, it is not uncommon to find that the catheter becomes coated with a bacterial-produced “slime” that protects the organism from the immune system and makes eradication of the infection difficult. Therefore, the treatments of most infections require shunt removal (and often placement of a temporary external ventricular shunt to relieve hydrocephalus) in addition to systemic and/or intraventricular antibiotic therapy. Poor therapeutic results tend to occur if the shunt is left in place during treatment. Antibiotic therapy is complicated by the fact that many antibiotics do not cross the blood-brain barrier effectively.

[0282]

An effective CNS shunt coating would reduce the incidence of complications such as ventriculitis, ventricular compartmentalization, meningitis, subdural empyema, nephritis (with VA shunts), seizures, cortical mantle thinning, mental retardation or death. An effective coating would also decrease the number of CNS shunts requiring replacement, resulting in lower mortality and morbidity for patients with these implants.

[0283]

In a preferred embodiment, an anthracycline (e.g., doxorubicin and mitoxantrone), fluoropyrimidine (e.g., 5-FU), folic acid antagonist (e.g., methotrexate), and/or podophylotoxin (e.g., etoposide) is formulated into a coating applied to the surface of the components of the CNS shunt. The drug(s) can be applied in several manners: (a) as a coating applied to the external surface of the shunt; (b) as a coating applied to the internal (luminal) surface of the shunt; and/or (c) as a coating applied to all or parts of both surfaces.

[0284]

Drug-coating of, or drug incorporation into CNS shunts will allow bacteriocidal drug levels to be achieved locally on the shunt surface, thus reducing the incidence of bacterial colonization and subsequent development of infectious complications, while producing negligible systemic exposure to the drugs. Although for some agents polymeric carriers are not required for attachment of the drug, several polymeric carriers are particularly suitable for use in this embodiment. Of particular interest are polymeric carriers such as polyurethanes (e.g., ChronoFlex AL 85A [CT Biomaterials], HydroMed640™ [CT Biomaterials], HYDROSLIP C™ [CT Biomaterials], HYDROTHANE™ [CT Biomaterials]), acrylic or methacrylic copolymers (e.g. poly(ethylene-co-acrylic acid), cellulose-derived polymers (e.g. nitrocellulose, Cellulose Acetate Butyrate, Cellulose acetate propionate), acrylate and methacrylate copolymers (e.g. poly(ethylene-co-vinyl acetate)) as well as blends thereof.

[0285]

As CNS shunts are made in a variety of configurations and sizes, the exact dose administered will vary with device size, surface area, design and portions of the shunt coated. However, certain principles can be applied in the application of this art. Drug dose can be calculated as a function of dose per unit area (of the portion of the device being coated), total drug dose administered can be measured and appropriate surface concentrations of active drug can be determined. Regardless of the method of application of the drug to the CNS shunt, the preferred anticancer agents, used alone or in combination, should be administered under the following dosing guidelines:

[0286]

(a) Anthracyclines. Utilizing the anthracycline doxorubicin as an example, whether applied as a polymer coating, incorporated into the polymers which make up the CNS shunt components (such as Dacron or Teflon), or applied without a carrier polymer, the total dose of doxorubicin applied should not exceed 25 mg (range of 0.1 μg to 25 mg). In a particularly preferred embodiment, the total amount of drug applied should be in the range of 1 μg to 5 mg. The dose per unit area (i.e. the amount of drug as a function of the surface area of the portion of the CNS shunt to which drug is applied and/or incorporated) should fall within the range of 0.01 μg-100 μg per mm2 of surface area. In a particularly preferred embodiment, doxorubicin should be applied to the CNS shunt surface at a dose of 0.1 μg/mm2-10 μg/mm2. As different polymer and non-polymer coatings will release doxorubicin at differing rates, the above dosing parameters should be utilized in combination with the release rate of the drug from the CNS shunt surface such that a minimum concentration of 10−7 -10−4 M of doxorubicin is maintained on the surface. It is necessary to insure that surface drug concentrations exceed concentrations of doxorubicin known to be lethal to multiple species of bacteria and fungi (i.e.. are in excess of 10−4 M; although for some embodiments lower concentrations are sufficient). In a preferred embodiment, doxorubicin is released from the surface of the CNS shunt such that anti-infective activity is maintained for a period ranging from several hours to several months. In a particularly preferred embodiment the drug is released in effective concentrations for a period ranging from 1-12 weeks. It should be readily evident given the discussions provided herein that analogues and derivatives of doxorubicin (as described previously) with similar functional activity can be utilized for the purposes of this invention; the above dosing parameters are then adjusted according to the relative potency of the analogue or derivative as compared to the parent compound (e.g. a compound twice as potent as doxorubicin is administered at half the above parameters, a compound half as potent as doxorubicin is administered at twice the above parameters, etc.).

[0287]

Utilizing mitoxantrone as another example of an anthracycline, whether applied as a polymer coating, incorporated into the polymers which make up the CNS shunt (such as Dacron or Teflon), or applied without a carrier polymer, the total dose of mitoxantrone applied should not exceed 5 mg (range of 0.01 μg to 5 mg). In a particularly preferred embodiment, the total amount of drug applied should be in the range of 0.1 μg to 1 mg. The dose per unit area (i.e. the amount of drug as a function of the surface area of the portion of the CNS shunt to which drug is applied and/or incorporated) should fall within the range of 0.01 μg-20 μg per mm2 of surface area. In a particularly preferred embodiment, mitoxantrone should be applied to the CNS shunt surface at a dose of 0.05 μg/mm2-3 μg/mm2. As different polymer and non-polymer coatings will release mitoxantrone at differing rates, the above dosing parameters should be utilized in combination with the release rate of the drug from the CNS shunt surface such that a minimum concentration of 10−5-10−6 M of mitoxantrone is maintained. It is necessary to insure that drug concentrations on the surface exceed concentrations of mitoxantrone known to be lethal to multiple species of bacteria and fungi (i.e. are in excess of 10−5 M; although for some embodiments lower drug levels will be sufficient). In a preferred embodiment, mitoxantrone is released from the CNS shunt surface such that anti-infective activity is maintained for a period ranging from several hours to several months. In a particularly preferred embodiment the drug is released in effective concentrations for a period ranging from 1-12 weeks. It should be readily evident based upon the discussion provided herein that analogues and derivatives of mitoxantrone (as described previously) with similar functional activity can be utilized for the purposes of this invention; the above dosing parameters are then adjusted according to the relative potency of the analogue or derivative as compared to the parent compound (e.g. a compound twice as potent as mitoxantrone is administered at half the above parameters, a compound half as potent as mitoxantrone is administered at twice the above parameters, etc.).

[0288]

(b) Fluoropyrimidines Utilizing the fluoropyrimidine 5-fluorouracil as an example, whether applied as a polymer coating, incorporated into the polymers which make up the CNS shunt (such as Dacron or Teflon), or applied without a carrier polymer, the total dose of 5-fluorouracil applied should not exceed 250 mg (range of 1.0 μg to 250 mg). In a particularly preferred embodiment, the total amount of drug applied should be in the range of 10 μg to 25 mg. The dose per unit area (i.e. the amount of drug as a function of the surface area of the portion of the CNS shunt to which drug is applied and/or incorporated) should fall within the range of 0.1 μg-1 mg per mm2 of surface area. In a particularly preferred embodiment, 5-fluorouracil should be applied to the CNS shunt surface at a dose of 1.0 μg/mm2-50 μg/mm2. As different polymer and non-polymer coatings will release 5-fluorouracil at differing rates, the above dosing parameters should be utilized in combination with the release rate of the drug from the CNS shunt surface such that a minimum concentration of 10−4-10−7 M of 5-fluorouracil is maintained. It is necessary to insure that surface drug concentrations exceed concentrations of 5-fluorouracil known to be lethal to numerous species of bacteria and fungi (i.e., are in excess of 10−4 M; although for some embodiments lower drug levels will be sufficient). In a preferred embodiment, 5-fluorouracil is released from the CNS shunt surface such that anti-infective activity is maintained for a period ranging from several hours to several months. In a particularly preferred embodiment the drug is released in effective concentrations for a period ranging from 1-12 weeks. It should be readily evident based upon the discussion provided herein that analogues and derivatives of 5-fluorouracil (as described previously) with similar functional activity can be utilized for the purposes of this invention; the above dosing parameters are then adjusted according to the relative potency of the analogue or derivative as compared to the parent compound (e.g. a compound twice as potent as 5-fluorouracil is administered at half the above parameters, a compound half as potent as 5-fluorouracil is administered at twice the above parameters, etc.).

[0289]

(c) Podophylotoxins Utilizing the podophylotoxin etoposide as an example, whether applied as a polymer coating, incorporated into the polymers which make up the CNS shunt (such as Dacron or Teflon), or applied without a carrier polymer, the total dose of etoposide applied should not exceed 25 mg (range of 0.1 μg to 25 mg). In a particularly preferred embodiment, the total amount of drug applied should be in the range of 1 μg to 5 mg. The dose per unit area (i.e. the amount of drug as a function of the surface area of the portion of the CNS shunt to which drug is applied and/or incorporated) should fall within the range of 0.01 μg-100 μg per mm2 of surface area. In a particularly preferred embodiment, etoposide should be applied to the CNS shunt surface at a dose of 0.1 μg/mm2-10 μg/mm2. As different polymer and non-polymer coatings will release etoposide at differing rates, the above dosing parameters should be utilized in combination with the release rate of the drug from the CNS shunt surface such that a concentration of 10−5-10−6 M of etoposide is maintained. It is necessary to insure that surface drug concentrations exceed concentrations of etoposide known to be lethal to a variety of bacteria and fungi (i.e. are in excess of 10−5 M; although for some embodiments lower drug levels will be sufficient). In a preferred embodiment, etoposide is released from the surface of the CNS shunt such that anti-infective activity is maintained for a period ranging from several hours to several months. In a particularly preferred embodiment the drug is released in effective concentrations for a period ranging from 1-12 weeks. It should be readily evident based upon the discussion provided herein that analogues and derivatives of etoposide (as described previously) with similar functional activity can be utilized for the purposes of this invention; the above dosing parameters are then adjusted according to the relative potency of the analogue or derivative as compared to the parent compound (e.g. a compound twice as potent as etoposide is administered at half the above parameters, a compound half as potent as etoposide is administered at twice the above parameters, etc.).

EVD and ICP monitoring devices are also used in the management of hydrocephalus. The therapeutic agents, doses, coatings and release kinetics for the development of drug-coated EVD's and drug-coated ICP monitoring devices are identical to those described for CNS shunts.

K. Infections of Orthopedic Implants

[0292]

Implanted orthopedic devices such as prosthetic joints such as hip, knee, elbow, shoulder, wrist, metacarpal, and metatarsal prosthetics are subject to complications as a result of infection of the implant. Orthopedic implant infection has a variety of sequela including pain, immobility, failure of the prosthetic itself, loss/removal the of prosthetic, reoperation, loss of the affected limb or even death. The cost of treating each infection exceeds the cost of the primary joint arthroplasty itself by 3 or 4-fold (in excess of $50,000/case). Other orthopedic implant hardware such as internal and external fixation devices, plates and screws are also subject to such infection and infection-related complications. The present treatment includes multiple operations to remove infected prosthetics, with its own inherent risks, combined with antibiotic use.

[0293]

The rate of orthopedic prosthetic infection is highest in the first month post operatively then declines continuously there after. As an example, the combined incidence of rate of prosthetic joint infection for 2 years is approximately 5.9% per 1,000 joints; the rate then drops to 2.3% per 1,000 joints from year 2 to 10. The rate of infection also varies depending on the joint. Knee prosthetics are infected twice as frequently as hips. Shoulder prosthetic infections range from 0.5% to 3%, elbows up to 12%, wrists 1.5% to 5.0% and ankles 1.4% to 2.4%.

[0294]

There are three main mechanisms of infection. The most common is colonization of the implant (prosthetic, fixation plate, screws—any implantable orthopedic device) at the time of implant, either directly or through airborne contamination of the wound. The second method is spread from an adjacent focus of infection, such as wound infection, abscess or sinus tract. The third is hematogenous seeding during a systemic bacteremia, likely accounting for approximately 7% of all implant infections.

[0295]

Risk factors are multiple. The host may be compromised as a result of a systemic condition, an illness, a local condition, or as a result of medications that decrease the host defence capability. There is also a predisposition to infections if the patient has had prior surgery, perioperative wound compilations, or rheumatoid arthritis. Repeat surgical procedures increase the likelihood of infection as there is a reported 8-fold elevated risk of infection as compared to the primary prosthetic replacement procedure. The presence of a deep infection increases the risk of prosthetic infection 6-fold. Various diseases also increase the risk of infection. For example, rheumatoid arthritis patients have a higher risk of infection possibly as a result of medications that compromising their immunocompetency, while psoriatic patients have a higher rate possibly mediated by a compromised skin barrier that allows entry of microbes.

[0296]

The implant itself, and the cements that secure it in place, can cause a local immunocompromised condition that is poorly understood. Different implant materials have their own inherent rate of infection. For example, a metal-to-metal hinged prosthetic knee has 20-times the risk of infection of a metal-to-plastic knee.

[0297]

An implanted device is most susceptible to infection early on. Rabbit models have shown that only a few Staphylococcus aureus inoculated at the time of implant are required to cause an infection, but bacteremic (hematogenous) seeding at 3 weeks postoperatively is substantially more difficult and requires significantly more bacteria. This emphasizes the importance of an antimicrobial strategy initiated early at the time of implantation.

[0298]

Sixty five percent of all prosthetic joint infections are caused by gram positive cocci, (Staphylococcus aureus, Coagulase Negative Staphylococci, Beta-Hemolytic Streptococcus, Viridans Group Streptococci) and enterococci. Often multiple strains of staphylococcus can be present in a single prosthetic infection. Other organisms include aerobic gram negative bacilli, Enterobacteriacea, Pseudomonas aeruginosa and Anaerobes (such as Peptostreptococcus and Bacteroides species). Polymicrobial infections account for 12% of infections.

[0299]

The diagnosis of an infected implant is difficult due to the highly variable presentation; fever, general malaise, swelling, erythema, joint pain, loosening of the implant, or even acute septicemia. Fulminate presentations are typically caused by more virulent organisms such as Stapylococcus arureus and pyogneic beta-hemolytic streptococci. Chronic indolent courses are more typical of coagulase-negative staphylococci.

[0300]

Management of an infected orthopedic implant usually requires prolonged use of antibiotics and surgery to remove the infected device. Surgery requires debridement of the infected tissue, soft tissue, bone, cement, and removal of the infected implant. After a period of prolonged antibiotic use (weeks, months and sometimes a year to ensure microbial eradication), it is possible to implant a replacement prosthesis. Some authors advocate the use of antibiotic impregnated cement, but cite concerns regarding the risk of developing antibiotic resistance; especially methecillin resistance. If bone loss is extensive, an arthrodesis is often performed and amputation is necessary in some cases. Even when an infection is eradicated, the patient can be left severely compromised physically, have significant pain and carry a high risk of re-infection.

[0301]

It is therefore extremely clinically important to develop orthopedic implants capable of resisting or reducing the rate of infection. An effective orthopedic implant coating would reduce the incidence of joint and hardware infection; lower the incidence of prosthetic failure, sepsis, amputation and even death; and also decrease the number of orthopedic implants requiring replacement, resulting in lower morbidity for patients with these implants.

[0302]

In a preferred embodiment, doxorubicin, mitoxantrone, 5-fluorouracil and/or etoposide are formulated into a coating applied to the surface of the components of the orthopedic implant. The drug(s) can be applied in several manners: (a) as a coating applied to the external intraosseous surface of the prosthesis; (b) as a coating applied to the external (articular) surface of the prosthesis; (c) as a coating applied to all or parts of both surfaces; (d) as a coating applied to the surface of the orthopedic hardware (plates, screws, etc); (e) incorporated into the polymers which comprise the prosthetic joints (e.g. articular surfaces and other surface coatings) and hardware (e.g. polylactic acid screws and plates); and/or (f) incorporated into the components of the cements used to secure the orthopedic implants in place.

[0303]

Drug-coating of, or drug incorporation into orthopedic implant will allow bacteriocidal drug levels to be achieved locally on the implant surface, thus reducing the incidence of bacterial colonization and subsequent development of infectious complications, while producing negligible systemic exposure to the drugs. Although for some agents polymeric carriers are not required for attachment of the drug, several polymeric carriers are particularly suitable for use in this embodiment. Of particular interest are polymeric carriers such as polyurethanes (e.g., ChronoFlex AL 85A [CT Biomaterials], HydroMed640™ [CT Biomaterials], HYDROSLIP C™ [CT Biomaterials], HYDROTHANE™ [CT Biomaterials]), acrylic or methacrylic copolymers (e.g. poly(ethylene-co-acrylic acid), cellulose-derived polymers (e.g. nitrocellulose, Cellulose Acetate Butyrate, Cellulose acetate propionate), acrylate and methacrylate copolymers (e.g. poly(ethylene-co-vinyl acetate)) as well as blends thereof.

[0304]

The drugs of interest can also be incorporated into calcium phosphate or hydroxyapatite coatings on the medical devices.

[0305]

As orthopedic implants are made in a variety of configurations and sizes, the exact dose administered will vary with implant size, surface area, design and portions of the implant coated. However, certain principles can be applied in the application of this art. Drug dose can be calculated as a function of dose per unit area (of the portion of the implant being coated), total drug dose administered can be measured and appropriate surface concentrations of active drug can be determined. Regardless of the method of application of the drug to the orthopedic implant, the preferred anticancer agents, used alone or in combination, should be administered under the following dosing guidelines:

[0306]

(a) Anthracyclines. Utilizing the anthracycline doxorubicin as an example, whether applied as a polymer coating, incorporated into the polymers which make up the orthopedic implant components, or applied without a carrier polymer, the total dose of doxorubicin applied should not exceed 25 mg (range of 0.1 μg to 25 mg). In a particularly preferred embodiment, the total amount of drug applied should be in the range of 1 μg to 5 mg. The dose per unit area (i.e. the amount of drug as a function of the surface area of the portion of the orthopedic implant to which drug is applied and/or incorporated) should fall within the range of 0.01 μg-100 μg per mm of surface area. In a particularly preferred embodiment, doxorubicin should be applied to the orthopedic implant surface at a dose of 0.1 μg/mm2-10 μg/mm2. As different polymer and non-polymer coatings will release doxorubicin at differing rates, the above dosing parameters should be utilized in combination with the release rate of the drug from the orthopedic implant surface such that a minimum concentration of 10−7-10−4 M of doxorubicin is maintained on the surface. It is necessary to insure that surface drug concentrations exceed concentrations of doxorubicin known to be lethal to multiple species of bacteria. and fungi (i.e., are in excess of 10−4 M; although for some embodiments lower concentrations are sufficient). In a preferred embodiment, doxorubicin is released from the surface of the orthopedic implant such that anti-infective activity is maintained for a period ranging from several hours to several months. As described previously, the risk of infectious contamination of the implant is greatest over the first 3 days. Therefore, in a particularly preferred embodiment, the majority (or all) of the drug is released over the first 72 hours to prevent infection while allowing normal healing to occur thereafter. It should be readily evident based upon the discussion provided herein that analogues and derivatives of doxorubicin (as described previously) with similar functional activity can be utilized for the purposes of this invention; the above dosing parameters are then adjusted according to the relative potency of the analogue or derivative as compared to the parent compound (e.g., a compound twice as potent as doxorubicin is administered at half the above parameters, a compound half as potent as doxorubicin is administered at twice the above parameters, etc.).

[0307]

Utilizing mitoxantrone as another example of an anthracycline, whether applied as a polymer coating, incorporated into the polymers which make up the orthopedic implant, or applied without a carrier polymer, the total dose of mitoxantrone applied should not exceed 5 mg (range of 0.01 μg to 5 mg). In a particularly preferred embodiment, the total amount of drug applied should be in the range of 0.1 μg to 1 mg. The dose per unit area (i.e. the amount of drug as a function of the surface area of the portion of the orthopedic implant to which drug is applied and/or incorporated) should fall within the range of 0.01 μg-20 μg per mm2 of surface area. In a particularly preferred embodiment, mitoxantrone should be applied to the orthopedic implant surface at a dose of 0.05 μg/mm2-3 μg/mm2. As different polymer and non-polymer coatings will release mitoxantrone at differing rates, the above dosing parameters should be utilized in combination with the release rate of the drug from the orthopedic implant surface such that a minimum concentration of 10−5-10−6 M of mitoxantrone is maintained. It is necessary to insure that drug concentrations on the surface exceed concentrations of mitoxantrone known to be lethal to multiple species of bacteria and fungi (i.e. are in excess of 10−5 M; although for some embodiments lower drug levels will be sufficient). In a preferred embodiment, mitoxantrone is released from the orthopedic implant surface such that anti-infective activity is maintained for a period ranging from several hours to several months. As described previously, the risk of infectious contamination of the implant is greatest over the first 3 days. Therefore, in one embodiment, the majority (or all) of the drug is released over the first 72 hours to prevent infection while allowing normal healing to occur thereafter. It should be readily evident based upon the discussion provided herein that analogues and derivatives of mitoxantrone (as described previously) with similar functional activity can be utilized for the purposes of this invention; the above dosing parameters are then adjusted according to the relative potency of the analogue or derivative as compared to the parent compound (e.g. a compound twice as potent as mitoxantrone is administered at half the above parameters, a compound half as potent as mitoxantrone is administered at twice the above parameters, etc.).

[0308]

(b) Fluoropyrimidines Utilizing the fluoropyrimidine 5-fluorouracil as an example, whether applied as a polymer coating, incorporated into the polymers which make up the orthopedic implant, or applied without a carrier polymer, the total dose of 5-fluorouracil applied should not exceed 250 mg (range of 1.0 μg to 250 mg). In a particularly preferred embodiment, the total amount of drug applied should be in the range of 10 μg to 25 mg. The dose per unit area (i.e. the amount of drug as a function of the surface area of the portion of the orthopedic implant to which drug is applied and/or incorporated) should fall within the range of 0.1 μg-1 mg per mm2 of surface area. In a particularly preferred embodiment, 5-fluorouracil should be applied to the orthopedic implant surface at a dose of 1.0 μg/mm2-50 μg/mm2. As different polymer and non-polymer coatings will release 5-fluorouracil at differing rates, the above dosing parameters should be utilized in combination with the release rate of the drug from the orthopedic implant surface such that a minimum concentration of 10−4-10−7 M of 5-fluorouracil is maintained. It is necessary to insure that surface drug concentrations exceed concentrations of 5-fluorouracil known to be lethal to numerous species of bacteria and fungi (ie., are in excess of 10−4 M; although for some embodiments lower drug levels will be sufficient). In a preferred embodiment, 5-fluorouracil is released from the orthopedic implant surface such that anti-infective activity is maintained for a period ranging from several hours to several months. As described previously, the risk of infectious contamination of the implant is greatest over the first 3 days. Therefore, in a particularly preferred embodiment, the majority (or all) of the drug is released over the first 72 hours to prevent infection while allowing normal healing to occur thereafter. It should be readily evident based upon the discussion provided herein that analogues and derivatives of 5-fluorouracil (as described previously) with similar functional activity can be utilized for the purposes of this invention; the above dosing parameters are then adjusted according to the relative potency of the analogue or derivative as compared to the parent compound (e.g. a compound twice as potent as 5-fluorouracil is administered at half the above parameters, a compound half as potent as 5-fluorouracil is administered at twice the above parameters, etc.).

[0309]

(c) Podophylotoxins Utilizing the podophylotoxin etoposide as an example, whether applied as a polymer coating, incorporated into the polymers which make up the orthopedic implant, or applied without a carrier polymer, the total dose of etoposide applied should not exceed 25 mg (range of 0.1 μg to 25 mg). In a particularly preferred embodiment, the total amount of drug applied should be in the range of 1 μg to 5 mg. The dose per unit area (i.e. the amount of drug as a function of the surface area of the portion of the orthopedic implant to which drug is applied and/or incorporated) should fall within the range of 0.01 μg-100 μg per mm2 of surface area. In a particularly preferred embodiment, etoposide should be applied to the orthopedic implant surface at a dose of 0.1 μg/mm2-10 μg/mm2. As different polymer and non-polymer coatings will release etoposide at differing rates, the above dosing parameters should be utilized in combination with the release rate of the drug from the orthopedic implant surface such that a concentration of 10−5-10−6 M of etoposide is maintained. It is necessary to insure that surface drug concentrations exceed concentrations of etoposide known to be lethal to a variety of bacteria and fungi (i.e. are in excess of 10−5 M; although for some embodiments lower drug levels will be sufficient). In a preferred embodiment, etoposide is released from the surface of the orthopedic implant such that anti-infective activity is maintained for a period ranging from several hours to several months. As described previously, the risk of infectious contamination of the implant is greatest over the first 3 days. Therefore, in a particularly preferred embodiment, the majority (or all) of the drug is released over the first 72 hours to prevent infection while allowing normal healing to occur thereafter. It should be readily evident based upon the discussion provided herein that analogues and derivatives of etoposide (as described previously) with similar functional activity can be utilized for the purposes of this invention; the above dosing parameters are then adjusted according to the relative potency of the analogue or derivative as compared to the parent compound (e.g. a compound twice as potent as etoposide is administered at half the above parameters, a compound half as potent as etoposide is administered at twice the above parameters, etc.).

The drug-coating, dosing, surface concentrations and release kinetics of these implants is identical to the embodiment described above for orthopedic implants. In addition, doxorubicin, mitoxantrone, 5-fluorouracil and/or etoposide can be added to solutions used in medicine (storage solutions, irrigation fluids, saline, mannitol, glucose solutions, lipids, nutritional fluids, and anaesthetic solutions) to prevent infection transmitted via infected solutions/fluids used in patient management.

M. Infections Associated with Ocular Implants

[0313]

The principle infections of medical device implants in the eye are endophthalmitis associated with intraocular lens implantation for cataract surgery and corneal infections secondary to contact lens use.

[0314]

Infections of Intraocular Lenses

[0315]

The number of intraocular lenses implanted in the United States has grown exponentially over the last decade. Currently, over 1 million intraocular lenses are implanted annually, with the vast majority (90%) being placed in the posterior chamber of the eye. Endophthalmitis is the most common infectious complication of intraocular lens placement and occurs in approximately 0.3% of surgeries (3,000 cases per year). The vast majority are due to surgical contamination and have an onset within 48 hours of the procedure.

[0316]

The most common causes of endophthalmitis are Coagulase Negative Staphylococci (principally Staphylococcus epidermidis), Staphylococcus aureus, Enterococci, and Proteus mirabilis. Symptoms of the condition include blurred vision, ocular pain, headache, photophobia, and corneal edema. The treatment of endophthalmitis associated with cataract surgery includes vitrectomy and treatment with systemic and/or intravitreal antibiotic therapy. Although most cases do not require removal of the lens, in complicated cases, visual acuity can be permanently affected and/or the lens must be removed and replaced at a later date. An effective intraocular lens coating would reduce the incidence of endophthalmitis and also decrease the number of intraocular lens requiring replacement, resulting in lower morbidity for patients with these implants.

[0317]

In a preferred embodiment, doxorubicin, mitoxantrone, 5-fluorouracil and/or etoposide are formulated into a coating applied to the surface of the components of the intraocular lens. The drug(s) can be applied in several manners: (a) as a coating applied to the external surface of the lens; (b) as a coating applied to the internal (luminal) surface of the lens; (c) as a coating applied to all or parts of both surfaces of the lens; and/or (d) incorporated into the polymers which comprise the lens.

[0318]

Drug-coating of, or drug incorporation into intraocular lenses will allow bacteriocidal drug levels to be achieved locally on the lens surface, thus reducing the incidence of bacterial colonization and subsequent development of infectious complications, while producing negligible systemic exposure to the drugs. Although for some agents polymeric carriers are not required for attachment of the drug, several polymeric carriers are particularly suitable for use in this embodiment. Of particular interest are polymeric carriers such as polyurethanes (e.g., ChronoFlex AL 85A [CT Biomaterials], HydroMed640™ [CT Biomaterials], HYDROSLIP C™ [CT Biomaterials], HYDROTHANE™ [CT Biomaterials]), acrylic or methacrylic copolymers (e.g. poly(ethylene-co-acrylic acid), cellulose-derived polymers (e.g. nitrocellulose, Cellulose Acetate Butyrate, Cellulose acetate propionate), acrylate and methacrylate copolymers (e.g. poly(ethylene-co-vinyl acetate)) as well as blends thereof.

[0319]

As intraocular lenses are made in a variety of configurations and sizes, the exact dose administered will vary with lens size, surface area, design and portions of the lens coated. However, certain principles can be applied in the application of this art. Drug dose can be calculated as a function of dose per unit area (of the portion of the lens being coated), total drug dose administered can be measured and appropriate surface concentrations of active drug can be determined. Regardless of the method of application of the drug to the intraocular lens, the preferred anticancer agents, used alone or in combination, should be administered under the following dosing guidelines:

[0320]

(a) Anthracyclines. Utilizing the anthracycline doxorubicin as an example, whether applied as a polymer coating, incorporated into the polymers which make up the intraocular lens components, or applied without a carrier polymer, the total dose of doxorubicin applied should not exceed 25 mg (range of 0.1 μg to 25 mg). In a particularly preferred embodiment, the total amount of drug applied should be in the range of 1 μg to 5 mg. The dose per unit area (i.e. the amount of drug as a function of the surface area of the portion of the intraocular lens to which drug is applied and/or incorporated) should fall within the range of 0.01 μg-100 μg per mm2 of surface area. In a particularly preferred embodiment, doxorubicin should be applied to the intraocular lens surface at a dose of 0.1 μg/mm2-10 μg/mm2. As different polymer and non-polymer coatings will release doxorubicin at differing rates, the above dosing parameters should be utilized in combination with the release rate of the drug from the intraocular lens surface such that a minimum concentration of 10−7-10−4 M of doxorubicin is maintained on the surface. It is necessary to insure that surface drug concentrations exceed concentrations of doxorubicin known to be lethal to multiple species of bacteria and fungi (i.e., are in excess of 10−4 M; although for some embodiments lower concentrations are sufficient). In a preferred embodiment, doxorubicin is released from the surface of the intraocular lens such that anti-infective activity is maintained for a period ranging from several hours to several months. In a particularly preferred embodiment the drug is released in effective concentrations for a period ranging from 1-12 weeks. It should be readily evident based upon the discussion provided herein that analogues and derivatives of doxorubicin (as described previously) with similar functional activity can be utilized for the purposes of this invention; the above dosing parameters are then adjusted according to the relative potency of the analogue or derivative as compared to the parent compound (e.g. a compound twice as potent as doxorubicin is administered at half the above parameters, a compound half as potent as doxorubicin is administered at twice the above parameters, etc.).

[0321]

Utilizing mitoxantrone as another example of an anthracycline, whether applied as a polymer coating, incorporated into the polymers which make up the intraocular lens, or applied without a carrier polymer, the total dose of mitoxantrone applied should not exceed 5 mg (range of 0.01 μg to 5 mg). In a particularly preferred embodiment, the total amount of drug applied should be in the range of 0.1 μg to 1 mg. The dose per unit area (i.e. the amount of drug as a function of the surface area of the portion of the intraocular lens to which drug is applied and/or incorporated) should fall within the range of 0.01 μg-20 μg per mm2 of surface area. In a particularly preferred embodiment, mitoxantrone should be applied to the intraocular lens surface at a dose of 0.05 μg/mm2-3 μg/mm2. As different polymer and non-polymer coatings will release mitoxantrone at differing rates, the above dosing parameters should be utilized in combination with the release rate of the drug from the intraocular lens surface such that a minimum concentration of 10−5-10−6 M of mitoxantrone is maintained. It is necessary to insure that drug concentrations on the surface exceed concentrations of mitoxantrone known to be lethal to multiple species of bacteria and fungi (i.e. are in excess of 10−5 M; although for some embodiments lower drug levels will be sufficient). In a preferred embodiment, mitoxantrone is released from the intraocular lens surface such that anti-infective activity is maintained for a period ranging from several hours to several months. In a particularly preferred embodiment the drug is released in effective concentrations for a period ranging from 1-12 weeks. It should be readily evident based upon the discussion provided herein that analogues and derivatives of mitoxantrone (as described previously) with similar functional activity can be utilized for the purposes of this invention; the above dosing parameters are then adjusted according to the relative potency of the analogue or derivative as compared to the parent compound (e.g. a compound twice as potent as mitoxantrone is administered at half the above parameters, a compound half as potent as mitoxantrone is administered at twice the above parameters, etc.).

[0322]

(b) Fluoropyrimidines Utilizing the fluoropyrimidine 5-fluorouracil as an example, whether applied as a polymer coating, incorporated into the polymers which make up the intraocular lens, or applied without a carrier polymer, the total dose of 5-fluorouracil applied should not exceed 250 mg (range of 1.0 μg to 250 mg). In a particularly preferred embodiment, the total amount of drug applied should be in the range of 10 μg to 25 mg. The dose per unit area (i.e. the amount of drug as a function of the surface area of the portion of the intraocular lens to which drug is applied and/or incorporated) should fall within the range of 0.1 μg-1 mg per mm2 of surface area. In a particularly preferred embodiment, 5-fluorouracil should be applied to the intraocular lens surface at a dose of 1.0 μg/mm2-50 μg/mm2. As different polymer and non-polymer coatings will release 5-fluorouracil at differing rates, the above dosing parameters should be utilized in combination with the release rate of the drug from the intraocular lens surface such that a minimum concentration of 10−4-10−7 M of 5-fluorouracil is maintained. It is necessary to insure that surface drug concentrations exceed concentrations of 5-fluorouracil known to be lethal to numerous species of bacteria and fungi (i.e., are in excess of 10−4 M; although for some embodiments lower drug levels will be sufficient). In a preferred embodiment, 5-fluorouracil is released from the intraocular lens surface such that anti-infective activity is maintained for a period ranging from several hours to several months. In a particularly preferred embodiment the drug is released in effective concentrations for a period ranging from 1-12 weeks. It should be readily evident based upon the discussion provided herein that analogues and derivatives of 5-fluorouracil (as described previously) with similar functional activity can be utilized for the purposes of this invention; the above dosing parameters are then adjusted according to the relative potency of the analogue or derivative as compared to the parent compound (e.g. a compound twice as potent as 5-fluorouracil is administered at half the above parameters, a compound half as potent as 5-fluorouracil is administered at twice the above parameters, etc.).

[0323]

(c) Podophylotoxins Utilizing the podophylotoxin etoposide as an example, whether applied as a polymer coating, incorporated into the polymers which make up the intraocular lens, or applied without a carrier polymer, the total dose of etoposide applied should not exceed 25 mg (range of 0.1 μg to 25 mg). In a particularly preferred embodiment, the total amount of drug applied should be in the range of 1 μg to 5 mg. The dose per unit area (i.e. the amount of drug as a function of the surface area of the portion of the intraocular lens to which drug is applied and/or incorporated) should fall within the range of 0.01 μg-100 μg per mm2 of surface area. In a particularly preferred embodiment, etoposide should be applied to the intraocular lens surface at a dose of 0.1 μg/mm2-10 μg/mm2. As different polymer and non-polymer coatings will release etoposide at differing rates, the above dosing parameters should be utilized in combination with the release rate of the drug from the intraocular lens surface such that a concentration of 10−5-10−6 M of etoposide is maintained. It is necessary to insure that surface drug concentrations exceed concentrations of etoposide known to be lethal to a variety of bacteria and fungi (i.e. are in excess of 10−5 M; although for some embodiments lower drug levels will be sufficient). In a preferred embodiment, etoposide is released from the surface of the intraocular lens such that anti-infective activity is maintained for a period ranging from several hours to several months. In a particularly preferred embodiment the drug is released in effective concentrations for a period ranging from 1-12 weeks. It should be readily evident based upon the discussion provided herein that analogues and derivatives of etoposide (as described previously) with similar functional activity can be utilized for the purposes of this invention; the above dosing parameters are then adjusted according to the relative potency of the analogue or derivative as compared to the parent compound (e.g. a compound twice as potent as etoposide is administered at half the above parameters, a compound half as potent as etoposide is administered at twice the above parameters, etc.).

Contact lenses are primarily used for the correction of refractive errors, but are also used after cataract surgery (Aphakie lenses) and “bandage” lenses are used following corneal trauma. Over 24 million people wear contact lenses and many of them will suffer from ulcerative keratitis resulting from contact lens-associated infection. These infections are typically bacterial in nature, are secondary to corneal damage/defects, and are caused primarily by Gram Positive Cocci and Pseudomonas aeruginosa.

[0327]

The drug-coating of contact lenses is identical to the embodiment described above for intraocular lenses. In addition, doxorubicin, mitoxantrone, 5-fluorouracil and/or etoposide can be added to contact lens storage solution to prevent infection transmitted via infected cleaning/storage solutions.

[0328]

It should be readily evident to one of skill in the art that any of the previously mentioned agents, or derivatives and analogues thereof, can be utilized to create variation of the above compositions without deviating from the spirit and scope of the invention.

A coating solution is prepared by dissolving 20 g ChronoFlex Al 85A (CT Biomaterials) in 100 mL DMAC:THF (40:60) at 50° C. with stirring. Once dissolved, the polymer solution is cooled to room temperature. 20 mg mitoxantrone is added to 2 mL of the polyurethane solution. The solution is stirred until a homogenious mixture is obtained. Polyurethane 7 French tubing is dipped into the polymer/drug solution and then withdrawn. The coated tube is air dried (80° C.). The sample is then dried under vacuum to further reduce the residual solvent in the coating.

Example 3 Catheter—Dip Coating—Degradable Polymer

[0334]

A coating solution is prepared by dissolving 2 g PLG (50:50) in 10 mL dichloromethane:methanol (70:30). Once dissolved, 20mg mitoxantrone is added to the polymer solution. Once the solution is a homogeneous solution, polyurethane 7 French tubing is dipped into the solution and then withdrawn. The coated tube is air dried. The sample is then dried under vacuum to further reduce the residual solvent in the coating.

Example 4 Catheter—Dip Coating—Drug Only

[0335]

1 mL methanol is added to 20 mg mitoxantrone. Polyurethane 7 French tubing is dipped into the solution and then withdrawn. The coated tube is air dried. The sample is then dried under vacuum to further reduce the residual solvent in the coating.

Example 5 Catheter—Dip Coating—Drug Impregnation

[0336]

0.6 mL methanol is added to 20 mg mitoxantrone. 1.4 mL DMAC is added slowly. Polyurethane 7 French tubing is dipped into the solution. After various periods of time (2 min, 5 min, 10 min, 20 min, 30 min) the tube was withdrawn. The coated tube is air dried (80° C.). The sample is then dried under vacuum to further reduce the residual solvent in the coating.

Example 6 Tympanostomy Tubes—Dip Coating—Non-degradable Polymer

[0337]

A coating solution is prepared by dissolving 20 g ChronoFlex Al 85A (CT Biomaterials) in 100 mL DMAC:THF (50:50) at 50° C. with stirring. Once dissolved, the polymer solution is cooled to room temperature. 20 mg mitoxantrone is added to 2 mL of the polyurethane solution. The solution is stirred until a homogenious mixture is obtained. A stainless steel tympanostomy tube is dipped into the polymer/drug solution and then withdrawn. The coated tube is air dried (80° C.). The sample is then dried under vacuum to further reduce the residual solvent in the coating.

Example 7 Catheter—Dip Coating—Non-degradable Polymer

[0338]

A coating solution is prepared by dissolving 20 g ChronoFlex Al 85A (CT Biomaterials) in 100 mL THF at 50° C. with stirring. Once dissolved, the polymer solution is cooled to room temperature. 20 mg etoposide is added to 2 mL of the polyurethane solution. The solution is stirred until a homogenious mixture is obtained. Polyurethane 7 French tubing is dipped into the polymer/drug solution and then withdrawn. The coated tube is air dried (80 C.). The sample is then dried under vacuum to further reduce the residual solvent in the coating.

Example 8 Catheter—Dip Coating—Degradable Polymer

[0339]

A coating solution is prepared by dissolving 2 g PLG (50:50) in 10 mL dichloromethane:methanol (70:30). Once dissolved, 20 mg etoposide is added to the polymer solution. Once the solution is a homogeneous solution, polyurethane 7 French tubing is dipped into the solution and then withdrawn. The coated tube is air dried. The sample is then dried under vacuum to further reduce the residual solvent in the coating.

Example 9 Catheter—Dip Coating—Drug Only

[0340]

1 mL THF is added to 20 mg etoposide. Polyurethane 7 French tubing is dipped into the solution and then withdrawn. The coated tube is air dried. The sample is then dried under vacuum to further reduce the residual solvent in the coating.

Example 10 Catheter—Dip Coating—Drug Impregnation

[0341]

0.6 mL methanol is added to 1.4 mL DMAC which contains 20 mg etoposide. Polyurethane 7 French tubing is dipped into the solution. After various periods of time (2 min, 5 min, 10 min. 20 min, 30 min) the tube was withdrawn. The coated tube is air dried (80° C.). The sample is then dried under vacuum to further reduce the residual solvent in the coating.

Example 11 Tympanostomy Tubes—Dip Coating—Non-degradable Polymer

[0342]

A coating solution is prepared by dissolving 20 g ChronoFlex Al 85A (CT Biomaterials) in 100 mL DMAC:THF (50:50) at 50° C. with stirring. Once dissolved, the polymer solution is cooled to room temperature. 20 mg etoposide is added to 2 mL of the polyurethane solution. The solution is stirred until a homogenious mixture is obtained. A stainless steel tympanostomy tube is dipped into the polymer/drug solution and then withdrawn. The coated tube is air dried (80° C.). The sample is then dried under vacuum to further reduce the residual solvent in the coating.

A piece of polyurethane 7 French tubing, with and without an oxygen plasma pretreatment step, is dipped into a solution of 5% (w/w) poly(ethylene-co acrylic acid) in THF. The sample was dried at 45° C. for 3 hours. The coated tubing was then dipped into a water:methanol (30:70) solution that contained 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) and 20 mg/mL Doxorubicin. After various times (15 min, 30 min, 60 min 120 min) the tubing is removed from the solution and dried at 60° C. for 2 hours followed by vacuum drying for 24 hours.

Example 13 Covalent Attachment of Doxorubicin to a Device Surface

[0344]

A piece of polyurethane 7 French tubing that has undergone a oxygen plasma pretreatment step is dipped into a water:methanol (30:70) solution that contained 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) and 20 mg/mL Doxorubicin. After various times (15 min, 30 min, 60 min 120 min) the tubing is removed from the solution and dried at 60° C. for 2 hours followed by vacuum drying for 24 hours.

Example 14 Impregnation of 5-Fluorouracil into Polyurethane Catheter

[0345]

A solution was prepared by dissolving 100 mg of 5-Fluorouracil into 20 ml anhydrous methanol. Polyurethane catheter tubing was immersed in this solution for 16 hours. The catheter tubing was vacuum dried at 50° C. for 16 hours.

Example 15 Impregnation of Mitoxantrone into Polyurethane Catheter

[0346]

A solution was prepared by dissolving 20 mg of Mitoxantrone-2HCl into 20 ml anhydrous methanol. Polyurethane catheter tubing was immersed in this solution for 16 hours. The catheter tubing was vacuum dried at 50° C. for 16 hours.

Example 16 Impregnation of Doxorubicin into Polyurethane Catheter

[0347]

A solution was prepared by dissolving 20 mg of Doxorubicin-HCl into 20 ml anhydrous methanol. Polyurethane catheter tubing was immersed in this solution for 16 hours. The catheter tubing was vacuum dried at 50° C. for 16 hours.

Example 17 Polyurethane Dip Coating With 5-Fluorouracil

[0348]

A solution was prepared by dissolving 125 mg 5-Fluorouracil and 2.5 g of Chronoflex AL85A (CT Biomaterials) in 50 ml of THF at 55° C. The solution was cooled to room temperature. Polyurethane catheters were weighted at one end and dipped in solution and then removed immediately. This process was repeated three times with 1 minute drying time interval between each dipping process. The catheter tubing was vacuum dried at 50° C. for 16 hours.

A solution was prepared by dissolving 125 mg 5-Fluorouracil, 62.5 mg of palmitic acid, and 2.437 g of ChronoflexAL85A (CT Biomaterials) in 50 ml of THF at 55° C. The solution was cooled to room temperature. Polyurethane catheters were weighted at one end and dipped in solution and then removed immediately. This process was repeated three times with a 1 minute drying time interval between each dipping process. The catheter tubing was vacuum dried at 50° C. for 16 hours.

Example 19 Catheter Dip Coating With Nafion and Mitoxantrone

[0350]

Catheters are weighted at one end and dipped into 5% Nafion solution (Dupont) and then removed immediately. This process was repeated three times with a 1 minute drying time interval between each dipping process. The catheter tubing was dried at room temperature for 2 hours. A solution was prepared with 1 mg of mitoxantrone-2HCl in 40 ml of deionized water. The catheter tubing was immersed in the solution for 5 minutes, and then was washed with deionized water and dried at room temperature.

Example 20 Catheter Dip Coating With Nafion and Doxorubicin

[0351]

Catheters are weighted at one end and dipped into 5% Nafion solution (Dupont) and then removed immediately. This process was repeated three times with a 1 minute drying time interval between each dipping process. The catheter tubing was dried at room temperature for 2 hours. A solution was prepared with 1 mg of doxorubicin-HCl in 40 ml of deionized water. The catheter tubing was immersed in the solution for 5 minutes, and then was washed with deionized water and dried at room temperature.

Example 21 Preparation of Release Buffer

[0352]

The release buffer was prepared by adding 8.22 g sodium chloride, 0.32 g sodium phosphate monobasic (monohydrate) and 2.60 g sodium phosphate dibasic (anhydrous) to a beaker. 1 L HPLC grade water was added and the solution was stirred until all the salts were dissolved. If required, the pH of the solution was adjusted to pH 7.4±0.2 using either 0.1N NaOH or 0.1N phosphoric acid.

Example 22 Release Study to Determine Release Profile of the Therapeutic Agent From a Catheter

[0353]

A sample of the therapeutic agent-loaded catheter was placed in a 15 mL culture tube. 15 mL release buffer (Example 21) was added to the culture tube. The tube was sealed with a Teflon lined screw cap and was placed on a rotating wheel in a 37° C. oven. At various time point, the buffer is withdrawn from the culture tube and is replaced with fresh buffer. The withdrawn buffer is then analysed for the amount of therapeutic agent contained in this buffer solution.

Example 23 HPLC Analysis of Therapeutic Agents in Release Buffer

[0354]

The following chromatographic conditions were used to quantify the amount of the therapeutic agent in the release medium:

Run

Injection

Detection

Therapeutic

Flow Rate

Time

Volume

Wavelength

Agent

Column

Mobile Phase

(mL/min)

(min)

(μL)

(nm)

5-Fluorouracil

YMC ODS-AQ 150 × 4.6 mm, 5 μm

PBS, pH 6.8

1

8

100

268

Doxorubicin

ACE 5 (V02-742) 150 × 4 mm

20% CAN, 26% Methanol, 54%

PBS (pH 3.6)

1

10

10

254

Mitoxantrone

ACE 5 C18, 150 × 4 mm, 5 μm

Phosphate buffer (pH 2.3)

1

4

10

658

Example 24 Effect of Palmitic Acid on the Release Profile of 5-Fluorouracil From a Polyurethane Film

[0355]

A 25%(w/v) Chronoflex AL 85A (CT Biomaterials) solution was prepared in THF. 50 mg 5-fluorouracil was weighed into each of 4 glass scintillation vials. Various amount of palmitic acid were added to each vial. 20 mL of the polyurethane solution was added to each scintillation vial. The samples were rotated at 37° C. until the solids had all dissolved. Samples were then cast as films using a casting knife on a piece of release liner. Samples were air dried and then dried overnight under vacuum. A portion of these samples were used to perform release studies (Example 22). FIG. 1 show the effect of palmitic acid on the release profile of 5-fluorouracil.

An overnight bacterial culture was diluted 1 to 5 to a final volume of 5 mls fresh Mueller Hinton broth. Then 100 μl of the diluted bacterial culture were spread onto Mueller Hinton agar plates. A test material (e.g., catheter tubing), with or without drug, was placed on the center of the plate. For example, catheters are typically 1 cm long and about 3 mm in diameter (which may be made of polyurethane, silicon or other suitable material) and are loaded with drug either through dip-coating or through use of a drug-impregnated coating. The plates were incubated at 37° C. for 16-18 hours. The zone of clearing around a test material was then measured (e.g., the distance from the catheter to where bacterial growth is inhibited), which indicated the degree of bacterial growth prevention. Various bacterial strains that may be tested include, but are not limited to, the following: E. coli C498 UB1005, P. aeruginosa H187, S. aureus C622 ATCC 25923, and S. epidermidis C621.

[0357]

One cm polyurethane catheters coated with 5-fluorouracil at several concentrations (2.5 mg/mL and 5.0 mg/mL) were examined for their effect against S. aureus. The zone of inhibition around the catheters coated in a solution of 2.5 mg/mL 5-Fluorouracil and placed on Mueller Hinton agar plates as described above was 35×39 mm, and for the catheters coated in a solution of 5.0 mg/mL 5-Fluorouracil was 30×37 mm. Catheters without drug showed no zone of inhibition. These results demonstrate the efficacy of 5-fluorouracil coated on a catheter at inhibiting the growth of S. aureus.

[0358]

From the foregoing, it will be appreciated that, although specific embodiments of the invention have been described herein for purposes of illustration, various modifications may be made without deviating from the spirit and scope of the invention. Accordingly, the invention is not limited except as by the appended claims.

Claims (23)

2. The medical implant according to claim 1 wherein said implant is covered or coated in whole or in part with a composition comprising an anthracycline, fluoropyrimidine, folic acid antagonist, podophylotoxin, camptothecin, hydroxyurea, or platinum complex.

3. The medical implant according to claim 1 or 2 wherein said anthracycline is doxorubicin or mitoxantrone.

4. The medical implant according to claim 1 or 2 wherein said fluoropyrimidine is 5-fluorouracil.

5. The medical implant according to claim 1 or 2 wherein said folic acid antagonist is methotrexate.

6. The medical implant according to claim 1 or 2 wherein said podophylotoxin is etoposide.

7. The medical implant according to claim 2 wherein said composition further comprises a polymer.

8. The medical implant according to claim 7 wherein said polymer is a biodegrable or a non-biodegradable polymer.

9. The medical implant according to claim 7 wherein said polymer is a polyurethane.

10. The medical implant according to claim 7 wherein said polymer is a poly(lactide-co-glycolide).

11. The medical implant according to any one of claims 7 to 10 wherein said fluoropyrimidine is 5-fluorouracil.

13. A composition, comprising a polymer and an anthracycline, fluoropyrimidine, folic acid antagonist, podophylotoxin, camptothecin, hydroxyurea, or platinum complex, wherein said anthracycline, fluoropyrimidine, folic acid antagonist, podophylotoxin, camptothecin, hydroxyurea, or platinum complex is present in said composition at a concentration of less than 10−4 M.

14. The composition according to claim 13 wherein said anthracycline, fluoropyrimidine, folic acid antagonist, podophylotoxin, camptothecin, hydroxyurea, or platinum complex, wherein said anthracycline, fluoropyrimidine, folic acid antagonist, podophylotoxin, camptothecin, hydroxyurea, or platinum complex is present in said composition at a concentration of less than any one of 10−5 M, 10−6 M, or 10−7 M.

15. The composition according to claim 13 wherein said polymer is a biodegrable or a non-biodegradable polymer.

16. The medical implant according to claim 13 wherein said polymer is a polyurethane.

17. The medical implant according to claim 13 wherein said polymer is a poly(lactide-co-glycolide).

18. The composition according to any one of claims 13 to 17 wherein said fluoropyrimidine is 5-fluorouracil.

19. A method for reducing or inhibiting infection associated with a medical implant, comprising the step of introducing into a patient a medical implant which has been covered or coated with an anthracycline, fluoropyrimidine, folic acid antagonist, podophylotoxin, camptothecin, hydroxyurea, or platinum complex.

20. The method according to claim 19 wherein said fluoropyrimidine is 5-fluorouracil.